Novel compounds

ABSTRACT

The invention relates to compounds of formula (I) and related aspects.

FIELD OF THE INVENTION

The invention relates to novel compounds which are inhibitors of the mitochondrial permeability transition pore (mPTP). The invention also inter alia relates to such compounds for use as medicaments, in particular, the treatment or prevention of degenerative, neurodegenerative or mitochondrial disease or other diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect.

BACKGROUND TO THE INVENTION

The mitochondria permeability transition pore (mPTP) is a high conductance channel residing on the inner mitochondrial membrane that is activated under certain conditions of cellular stress, in particular excessive Ca²⁺ loading and oxidative stress. It is permeable to solutes with molecular mass <1.5 kDa, is voltage and Ca²⁺ dependent and exhibits a characteristic large conductance. Once activated, oxidative phosphorylation is uncoupled resulting in the loss of the mitochondria membrane potential and disrupted mitochondria metabolism. In addition, solutes enter the mitochondrial matrix resulting in swelling, eventual rupture of the outer membrane with consequent release of apoptotic factors as well as sequestered Ca²⁺, leading to eventual cell death via apoptosis or necrosis depending on the type and physiology of the cell. As such it has been implicated as a key pathological event in multiple degenerative and metabolic diseases.

Under normal physiological conditions mitochondria play a key role in regulating cellular Ca²⁺ homeostasis. Ca²⁺ entering the cell via cell surface channels, a common mechanism of cell signalling, is rapidly sequestered by mitochondria, preventing excessive and toxic Ca²⁺ accumulation in the cell cytoplasm. In cell types such as neurons, skeletal muscle myofibers and cardiomyocytes which undergo high levels of Ca²⁺ flux, this Ca²⁺ ‘buffering’ effect of mitochondria is critical to maintain cell health. However, there is a limit to the capacity of mitochondria to sequester Ca²⁺ and if intramitochondrial Ca²⁺ levels reach a certain threshold the Ca²⁺ sensitive mPTP is activated, resulting in collapse of the mitochondria and initiation of cell death. Activation of the mPTP in degenerative diseases may occur in a variety of ways depending on the disease, for example: 1) excessive Ca²⁺ entry into cells and overload of the mitochondria with Ca²⁺2) dysfunctional mitochondrial Ca²⁺ efflux mechanisms, in particular decreased activity of the Ca²⁺ efflux transporter NCLX resulting in Ca²⁺ overload 3) overactivity or upregulation of the Ca²⁺ uptake mechanisms in mitochondria 4) oxidative stress 5) sensitization of the mPTP due to compromised mitochondrial function i.e. mPTP activation at lower intramitochondrial concentrations of Ca²⁺6) excessive transfer of Ca²⁺ from the endoplasmic reticulum into the mitochondria at contact points between the two organelles known as mitochondria-associated-membranes.

While the properties and function of the mPTP can be studied in simple in vitro assays in isolated mitochondria, the molecular identity of the mPTP is not known. Multiple proteins have been proposed to comprise the pore forming complex, including the ATP synthase and the adenine nucleotide transporter (ANT) family of proteins but no single protein is widely accepted as being responsible for formation of the pore. However, the peptidyl prolyl cis-trans isomerase F (Ppif), also known as cyclophilin D, is well accepted to be a key regulator of the pore, though not forming a transmembrane channel in its own right. Genetic or pharmacological inhibition of Ppif significantly decreases the sensitivity of pore opening in response to Ca²⁺ loading and other mPTP activators. Genetic ablation or pharmacological inhibition of Ppif has therefore been utilised to evaluate involvement of the mPTP in pathological pathways in cell and animal disease models. In this way, inhibition of the mPTP has been shown to be protective in numerous models of disease, in particular those where Ca²⁺ dysregulation and oxidative stress are known to contribute to cellular degeneration. Notably, genetic knockout of Ppif was shown to be protective in various preclinical in vivo transgenic models of neurodegenerative disease including Alzheimer's disease, Parkinson's disease and motor neuron disease, demonstrating the therapeutic potential of mPTP inhibition. In each of these diseases, genetic mutations in particular proteins that cause inherited forms of disease (i.e. amyloid precursor protein, alpha-synuclein and superoxide dismutase 1 respectively), and are expressed in the mouse models, have been shown to cause either Ca²⁺ overload of the mitochondria or sensitization of the mPTP. Recent evidence suggests this may occur through a common mechanism in Alzheimer's, Parkinson's and Friedreich's ataxia. In each case, it has been reported that in cells expressing the mutated disease associated proteins (amyloid precursor protein, PINK1 and frataxin respectively), the activity or expression of the mitochondrial Ca²⁺ efflux transporter, NCLX, is decreased, resulting in Ca²⁺ overload of the mitochondria. In the case of Parkinson's disease, the pathological aggregated form of the protein alpha-synuclein, a common misfolded protein in sporadic and inherited cases of Parkinson's disease, has also been shown to sensitise and activate the mPTP.

Genetic ablation of Ppif has been shown to be beneficial in numerous other preclinical models of degenerative disease, therefore demonstrating the potential of mPTP inhibitors in Duchenne and congenital forms of muscular dystrophy, ischemia-reperfusion injury, bone repair, pancreatitis and inter alia other associated disorders.

In addition to the demonstrated benefit of Ppif inhibition in preclinical models, mPTP function has been shown to be dysregulated in multiple other disease indications. In particular, in a number of diseases the threshold for mPTP activation in response to Ca²⁺ loading appears to be sensitised suggesting that mPTP activation may occur aberrantly under physiological conditions and drive tissue degeneration. For example, in muscle mitochondria from elderly human muscle biopsies, the threshold for mPTP activation is reduced compared to healthy control. In these diseases, this sensitization of mPTP activity underlies additional rationale for the therapeutic potential of mPTP inhibitors.

mPTP inhibitors may also have therapeutic potential in other diseases whether mitochondrial dysfunction, oxidative stress, inflammatory stress or Ca²⁺ dysregulation occur during disease pathogenesis.

The discovery and development of inhibitors of the mPTP has largely been focussed on identification of Ppif inhibitors. Cyclosporin A (CsA), originally identified as an immunosuppressant by virtue of its inhibitory activity at calcineurin, was also found to inhibit Ppif as well as other members of the peptidyl prolyl cis-trans isomerase (Ppi) enzyme family. Several cyclosporin A derivatives e.g. Debio-25, NIM811 were subsequently developed that retained broad activity against the Ppi enzyme family without inhibiting calcineurin, however none of these progressed to market. To date, no potent brain penetrant selective Ppif inhibitors have been reported. Other more recent approaches to discover mPTP inhibitors, have utilised phenotypic screens in isolated mitochondria. These have successfully identified potent small molecule mPTP inhibitors with a Ppif-independent mode of action.

Yu et al., (2020, Cell, 183, 1-14) relates to the link between mPTP activation and the mechanism of TDP-43 proteinopathy such as TAR DNA-binding protein 43 (TDP-43) associated neurodegeneration. Cytoplasmic neuronal accumulation of the normally nuclear protein TDP-43 is a disease hallmark for almost all cases of ALS and 40-50% of Frontotemporal Lobar Degeneration (FTLD), with some familial cases caused by mutant forms of the protein. Both diseases are associated with a neuroinflammatory cytokine profile related to upregulation of NF-κB and type I IFN pathways, directly suggesting a role for TDP-43 in neuroinflammation. Mutant or overexpressed WT TDP-43 in neurons mis-localises to the mitochondria and induces the release of mitochondrial DNA (mtDNA) into the cytoplasm. This mtDNA then activates the immune sensor cGAS-STING triggering the induction of innate immune genes such as IL-6, TNFα, and interferons. Inhibition of the mPTP with cyclosporin A or via CypD knockout, prevents the TDP-43 induced release of mtDNA and subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING extends the survival of mutant mice expressing a mutant TDP-43. The data implicates mPTP activation in mediating the toxic effects of TDP-43 in ALS and other disease where either mutations in the TDP-43 gene causes disease or where TDP-43 proteinopathy is observed.

Jang et al., (2021 American Journal of Physiology: Renal physiology, doi: 10.1152/ajprenal.00171.2021. Epub ahead of print. PMID: 34396791) highlighted the potential therapeutic benefit of mPTP inhibition (via CypD knockout) in a mouse model a kidney fibrosis. Unilateral ureteral obstruction was used to induce kidney fibrosis in WT and CypD KO mice. Inflammation, proximal tubule atrophy and markers of fibrosis were reduced in the CypD KO mice versus WT. Measures of fibrosis included collagen deposition, α-SMA and TGFβ expression, and interstitial cell proliferation. This highlights the potential role of the mPTP in cell injury/death-mediated tissue remodelling and fibrogenesis. mPTP inhibitors may therefore be beneficial in diseases where fibrosis is a key pathological mechanism, e,g, chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis.

WO2010/049768 relates to acrylamido derivatives and their use as therapeutic agents, particularly for the prevention and/or treatment of diseases associated with the activity of the mPTP (see also Plyte et al. J. Med Chem. 2014, 57, 5333-47). Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455) relates to phenotypic screening for mPTP modulators using platelets and discloses further acrylamido derivatives, including (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide. CA2884607A1 relates to acrylamido and maleimide compounds which are said to be useful in the treatment of mitochondrial diseases.

When dosed orally, the bioavailability and systemic exposure of a drug are largely determined by the degree of absorption from the gastrointestinal tract and the extent of first-pass metabolism in the liver. Properties such as high solubility (as measured in phosphate-buffered saline (PBS) or in the more biologically relevant Fasted State Simulated Intestinal Fluid (FaSSIF)) and high metabolic stability (as measured in vitro in either isolated liver microsomes or in hepatocytes from rat and human) are therefore predictive of improved oral bioavailability and systemic exposure in patients.

There remains a need to find further compounds which are inhibitors of mPTP, and in particular those that combine inhibition of mPTP with other desirable pharmacological properties, such as improved oral bioavailability and/or improved systemic exposure.

SUMMARY OF THE INVENTION

The invention provides a compound of formula (I):

-   -   wherein:     -   R_(1a) is H or methyl;     -   R_(1b) is H or fluoro;     -   A is group (Aa), (Ab), (Ac) or (Ad):     -   wherein group (Aa) is:

-   -   wherein:         -   R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH),             C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkylene(4-7 membered             heterocycloalkyl), C₁₋₄ alkoxy, OC₁₋₄ alkylene(aryl), C₁₋₄             alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄             alkyleneO (4-7 membered heterocycloalkyl), C₁₋₄             alkyleneO(aryl), C₃₋₆ alkynyl or C₁₋₄ alkyleneO(C₃₋₆             alkynyl); wherein said aryl, heterocycloalkyl and cycloalkyl             are optionally substituted by 1, 2 or 3 substituents each             independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl,             C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo, CN, OH, NR_(2a)R_(2b),             SO₂R_(2c) and NHSO₂R_(2c);         -   R_(2a) is selected from H and C₁₋₄ alkyl;         -   R_(2b) is selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄             alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered             heterocycloalkyl;         -   R_(2c) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄             alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered             heterocycloalkyl;         -   each R₃ is independently halo, methyl, ethyl or n-propyl;         -   m is 0, 1, 2, 3 or 4;     -   wherein group (Ab) is:

-   -   wherein:         -   R₄ is H, C₁₋₄ alkyl or C₁₋₄ alkylene(aryl); wherein said             aryl is optionally substituted by 1, 2 or 3 substituents             each independently selected from C₁₋₄ alkyl, C₃₋₆             cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo, CN, OH,             NR_(4a)R_(4b), SO₂R_(4c) and NHSO₂R_(4c);         -   R_(4a) is selected from H and C₁₋₄ alkyl;         -   R_(4b) is selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄             alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered             heterocycloalkyl;         -   R_(4c) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄             alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered             heterocycloalkyl; R₅ is H or C₁₋₄ alkyl;         -   each R₆ is independently C₁₋₄ alkyl or halo;         -   n is 0, 1, 2 or 3;     -   wherein group (Ac) is:

-   -   wherein:         -   R₇ is C₁₋₄ alkyl, C₁₋₄ alkylene(OH) or C₁₋₄ alkyleneOC₁₋₄             alkyl;         -   o is 1 or 2;     -   wherein group (Ad) is:

-   -   wherein:         -   X is a bond, O or CH₂;         -   each R₈ is independently halo, C₁₋₄ alkyl, C₁₋₄ alkoxy OC₁₋₄             haloalkyl, OC₁₋₄ alkylene(C₃₋₆ cycloalkyl), OC₁₋₄             alkylene(4-7 membered heterocycloalkyl) or OH; wherein said             heterocycloalkyl and cycloalkyl are optionally substituted             by 1, 2 or 3 substituents independently selected from C₁₋₄             alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo,             CN, OH, NR_(8a)R_(8b), SO₂R_(8c) and NHSO₂R_(8c);         -   R_(8a) is selected from H and C₁₋₄ alkyl;         -   R_(8b) is selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄             alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered             heterocycloalkyl;         -   R_(8c) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄             alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered             heterocycloalkyl;         -   each R₉ is independently halo or C₁₋₄ alkyl;         -   p is 0, 1 or 2;         -   q is 0, 1, 2, 3 or 4;     -   wherein B is:

-   -   wherein:         -   R₁₀ is H, halo or C₁₋₄ alkyl;         -   D, E and F are each independently C(R₁₀); or one of D, E and             F is N and the two remaining D, E and F groups are             independently C(R₁₀); and         -   provided that the compound of formula (I) is not             (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide;     -   or a pharmaceutically acceptable salt and/or solvate thereof.

The invention also provides a compound of formula (I):

-   -   wherein:     -   R_(1a) is H or methyl;     -   R_(1b) is H or fluoro;     -   A is group (Aa), (Ab), (Ac) or (Ad):     -   wherein group (Aa) is:

-   -   wherein:         -   R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH),             C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkylene(4-7 membered             heterocycloalkyl), C₁₋₄ alkoxy, OC₁₋₄ alkylene(aryl), C₁₋₄             alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄             alkyleneO (4-7 membered heterocycloalkyl), C₁₋₄             alkyleneO(aryl), C₃₋₆ alkynyl or C₁₋₄ alkyleneO(C₃₋₆             alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl             may be optionally substituted by up to 3 substituents each             independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl,             C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo and CN;         -   each R₃ is independently halo, methyl, ethyl or n-propyl;         -   m is 0, 1, 2, 3 or 4;     -   wherein group (Ab) is:

-   -   wherein:         -   R₄ is H, C₁₋₄ alkyl or C₁₋₄ alkylene(aryl); wherein said             aryl may be optionally substituted by up to 3 substituents             each independently selected from C₁₋₄ alkyl, C₃₋₆             cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo and CN;         -   R₅ is H or C₁₋₄ alkyl;         -   each R₆ is independently C₁₋₄ alkyl or halo;         -   n is 0, 1, 2 or 3;     -   wherein group (Ac) is:

-   -   wherein:         -   R₇ is C₁₋₄ alkyl, C₁₋₄ alkylene(OH) or C₁₋₄ alkyleneOC₁₋₄             alkyl;         -   o is 1 or 2;     -   wherein group (Ad) is:

-   -   wherein:         -   X is a bond, O or CH₂;         -   each R₈ is independently halo, C₁₋₄ alkyl, C₁₋₄ alkoxy or             OH;         -   each R₉ is independently halo or C₁₋₄ alkyl;         -   p is 0, 1 or 2;         -   q is 0, 1, 2, 3 or 4;     -   wherein B is:

-   -   wherein:         -   R₁₀ is H, halo or C₁₋₄ alkyl;         -   D, E and F are each independently C(R₁₀); or one of D, E and             F is N and the two remaining D, E and F groups are             independently C(R₁₀); and         -   provided that the compound of formula (I) is not             (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide;     -   or a pharmaceutically acceptable salt and/or solvate thereof.

In one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In one embodiment, a compound of formula (I) is provided in the form of a solvate. In one embodiment, a compound of formula (I) is provided.

The invention further provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

The invention also provides a compound of formula (I), or pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

The invention also provides a method of preventing or treating a disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject.

Suitably the disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia and re-perfusion injury, metabolic diseases, inflammatory or autoimmune diseases, diseases of aging and renal diseases.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a mitochondrial disease.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a mitochondrial disease.

The invention also provides a method of preventing or treating a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration.

The invention also provides a method of treating or preventing a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with fibrosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with fibrosis.

The invention also provides a method of treating or preventing a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” as used herein, such as in C₁₋₄ alkyl, whether alone or forming part of a larger group, is a straight or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of C₁₋₄ alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl and sec-butyl. Reference to “propyl” includes n-propyl and iso-propyl. Reference to “butyl” includes n-butyl, iso-butyl, tert-butyl and sec-butyl.

The term “alkylene” as used herein, such as C₁₋₄ alkylene, whether alone or forming part of a larger group e.g. C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH), C₁₋₄ alkylene(C₃₋₆ cycloalkyl), OC₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkylene(4-7 membered heterocycloalkyl), OC₁₋₄ alkylene(4-7 membered heterocycloalkyl), C₁₋₄ alkoxy, OC₁₋₄ alkylene(aryl), C₁₋₄ alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl), C₁₋₄ alkyleneO(aryl) or C₁₋₄ alkyleneO(C₃₋₆ alkynyl), e.g. C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH), C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkylene(4-7 membered heterocycloalkyl), C₁₋₄ alkoxy, OC₁₋₄ alkylene(aryl), C₁₋₄ alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl), C₁₋₄ alkyleneO(aryl) or C₁₋₄ alkyleneO(C₃₋₆ alkynyl), is a bifunctional straight or branched fully saturated hydrocarbon group containing the specified number of carbon atoms. Examples of C₁₋₄ alkylene groups include methylene (i.e. —CH₂—), ethylene (i.e. —CH₂CH₂—) n-propylene (i.e. (—CH₂)₃—) and n-butylene (i.e. (—CH₂)₄—). A branched example of a C₁₋₄ alkylene group is i-propylene (i.e. —CH(Me)CH₂—).

The term C₁₋₄ alkylene(OH) means an C₁₋₄ alkyl group substituted by OH, such as CH₂OH.

The term “alkoxy” as used herein, such as in C₁₋₄ alkoxy, refers to an alkyl group (e.g. a C₁₋₄ alkyl group) as defined above, singularly bonded to an oxygen atom. Examples of C₁₋₄ alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy and 3-butoxy, especially methoxy.

The term ‘halo’ or ‘halogen’ as used herein, refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are bromine, fluorine and chlorine, especially fluorine.

The term “haloalkyl” as used herein, such as in C₁₋₄ haloalkyl, whether alone or forming part of a larger group such as OC₁₋₄ haloalkyl, is a straight or branched alkyl group containing the specified number of carbon atoms, substituted by one or more halo atoms, for example fluoromethyl (CH₂F), di-fluoromethyl (CHF₂), tri-fluoromethyl (CF₃), 1-fluoroethyl (CH₂FCH₂) and 2-fluoroethyl (CH₂CH₂F).

The term “cycloalkyl” as used herein, such as in C₃₋₆ cycloalkyl, whether alone or forming part of a larger group such as C₁₋₄ alkylene(C₃₋₆ cycloalkyl) or C₁₋₄ alkyleneOC₃₋₆ cycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of C₃₋₆ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular cyclopropyl. Optionally, the cycloalkyl may be substituted as defined herein.

The term “heterocycloalkyl” as used herein, such as in 4-7 membered heterocycloalkyl, whether alone or forming part of a larger group such as C₁₋₄ alkylene(4-7 membered heterocycloalkyl) and C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl), is a fully saturated hydrocarbon ring containing the specified number of ring atoms, wherein at least one of the carbon atoms is replaced by a heteroatom such as N, S or O. Optionally, the heterocycloalkyl may be substituted as defined herein.

Examples of 4-7 membered heterocycloalkyl groups include those comprising one heteroatom such as containing one heteroatom (e.g. nitrogen), or containing two or more heteroatoms (such as two heteroatoms e.g. two nitrogen atoms or one nitrogen atom and one oxygen atom). Examples of 4-7 membered heterocycloalkyl groups containing one nitrogen atom include azetidinyl, pyrrolidinyl, piperidinyl and azepanyl. Examples of 4-7 membered heterocycloalkyl groups containing two nitrogen atoms include diazetidinyl, imidazolidinyl, pyrazolidinyl, diazinanyl, and diazepanyl.

Other examples of 4-7 membered heterocycloalkyl groups include oxetanyl, thietanyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, triazinanyl, trioxanyl, trithianyl, oxepanyl, and thiepanyl.

The term “aryl” as used herein, whether alone or forming part of a larger group e.g. C₁₋₄ alkylene(aryl), OC₁₋₄ alkylene(aryl) or C₁₋₄ alkyleneO(aryl), refers to a phenyl ring. Optionally, the aryl may be substituted as defined herein.

The term “alkynyl” as used herein, such as in C₃₋₆ alkynyl, whether alone or forming part of a larger group such as C₁₋₄ alkyleneO(C₃₋₆ alkynyl), is a straight or branched divalent hydrocarbon chain with a least one carbon-carbon triple bond. Examples of C₃₋₆ alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl and hexynyl.

An example of C₁₋₄ alkylene(aryl) is CH₂Ph where Ph means phenyl. Examples of C₁₋₄ alkyleneOC₁₋₄ alkyl include CH₂OMe, CH₂OEt and CH₂OPr. Examples of C₁₋₄ alkyleneOC₃₋₆ cycloalkyl include CH₂O—C₃ cycloalkyl and CH₂O—C₄ cycloalkyl, for example CH₂O-cyclopropyl or CH₂O-cyclobutyl. Examples of C₁₋₄ alkylene(4-7 membered heterocycloalkyl) include CH₂ (4-membered heterocycloalkyl), for example CH₂-azetidinyl, CH₂CH₂-azetidinyl. Examples of C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl) include C₁₋₄ alkylOC₄ heterocycloalkyl, such as CH₂O-azetidinyl. An example of C₁₋₄ alkyleneO(C₃₋₆ alkynyl) is CH₂OCH₂C≡CH.

Where substituents are indicated as being optionally substituted in formula (I) in the embodiments and preferences set out below, the optional substituent may be attached to an available carbon atom, which means a carbon atom which is attached to a hydrogen atom i.e. a C—H group or the optional substituent may be attached to an available nitrogen atom, which means a nitrogen atom which is attached to a hydrogen atom i.e. a N—H group. The optional substituent replaces the hydrogen atom attached to the carbon atom or the hydrogen atom attached to the nitrogen atom.

In one embodiment, R_(1a) is H. In a second embodiment, R_(1a) is methyl.

In one embodiment, R_(1b) is H. In a second embodiment, R_(1b) is fluoro.

In one preferred embodiment, A is group (Aa):

In one embodiment R₂ is C₁₋₄ alkyl, such as methyl, ethyl, propyl or butyl, especially methyl; C₁₋₄ alkylene(aryl), such as benzyl; C₁₋₄ alkylene(OH), such as CH₂OH; C₁₋₄ alkyleneOC₁₋₄ alkyl, such as CH₂OMe, CH₂OEt or CH₂OPr, especially CH₂OMe; C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, such as CH₂O—C₃ cycloalkyl or CH₂O—C₄ cycloalkyl, for example CH₂O-cyclopropyl or CH₂O-cyclobutyl; C₁₋₄ alkyleneO(aryl), such as CH₂OPh; C₁₋₄ alkylene(4-7 membered heterocycloalkyl), such as CH₂ (4-membered heterocycloalkyl), for example CH₂-azetidinyl, or CH₂CH₂ (4-membered heterocyloalkyl) for example CH₂CH₂-azetidinyl; C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl) such as C₁₋₄ alkylOC₄ heterocycloalkyl, especially CH₂O-azetidinyl; or C₁₋₄ alkyleneO(C₃₋₆ alkynyl), such as CH₂OCH₂C≡CH. Suitably, R₂ is methyl, CH₂OH or CH₂OMe, in particular methyl.

The aryl, heterocycloalkyl and cycloalkyl groups present in R₂ may be optionally substituted by up to 3 substituents, such as 1, 2 or 3, such as 1 or 2, e.g. 1 substituent, each independently selected from C₁₋₄ alkyl, such as methyl; C₃₋₆ cycloalkyl, such as cyclopropyl; C₁₋₄ alkoxy, such as OMe; C₁₋₄ haloalkyl, such as CF₃; halo, such as chloro or fluoro; CN; OH; NR_(2a)R_(2b); SO₂R_(2c); and NHSO₂R_(2c). Suitably, the aryl, heterocycloalkyl and cycloalkyl groups present in R₂ may be optionally substituted by up to 3 substituents, such as 1, 2 or 3, such as 1 or 2, e.g. 1 substituent, each independently selected from C₁₋₄ alkyl, such as methyl; C₃₋₆ cycloalkyl, such as cyclopropyl; C₁₋₄ alkoxy, such as OMe; C₁₋₄ haloalkyl, such as CF₃; halo, such as chloro or fluoro; and CN. Suitably, the aryl, heterocycloalkyl and cycloalkyl groups present in R₂ may be optionally substituted by up to 3 substituents, such as 1, 2 or 3, such as 1 or 2, e.g. 1 substituent, each independently selected from OH; NR_(2a)R_(2b); SO₂R₂; and NHSO₂R_(2c).

In one embodiment R_(2a) is H. In a second embodiment R_(2a) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_(2a) is H or methyl.

In one embodiment, R_(2b) is H. In a second embodiment, R_(2b) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R_(2b) is C₃₋₆ cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl. In a fourth embodiment, R_(2b) is C₁₋₄ alkoxy, such as OMe or OEt, especially OMe. In a fifth embodiment, R_(2b) is C₁₋₄ haloalkyl, such as CF₃. In a sixth embodiment, R_(2b) is aryl, such as phenyl. In a seventh embodiment, R_(2b) is 4-7 membered heterocycloalkyl, such as azetidinyl or oxetanyl. In an eighth embodiment, R_(2b) is H or methyl.

In one embodiment R_(2c) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a second embodiment, R_(2c) is C₃₋₆ cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl. In a third embodiment, R_(2c) is C₁₋₄ alkoxy, such as OMe or OEt, especially OMe. In a fourth embodiment, R_(2c) is C₁₋₄ haloalkyl, such as CF₃. In a fifth embodiment, R_(2c) is aryl, such as phenyl. In a sixth embodiment, R_(2c) is 4-7 membered heterocycloalkyl, such as azetidinyl or oxetanyl. In a seventh embodiment, R_(2c) is methyl.

Suitably, the aryl is substituted by 1, 2 or 3 substituents, such as 1 or 2, e.g. 1 substituent, each independently selected from methyl, chloro and fluoro. In one embodiment, the aryl is not substituted.

Suitably, the heterocycloalkyl is substituted by 1, 2 or 3 substituents, such as 1 or 2, e.g. 1 substituent, each independently selected from CH₂CH₂F (particularly as a substituent on a nitrogen atom) and fluoro (particularly as a substituent on a carbon atom). In one embodiment, the heterocycloalkyl is not substituted.

Suitably, when the heterocycloalkyl is azetidinyl, the nitrogen atom is in the 1-position or the 3-position (i.e. 1-azetidinyl or 3-azetidinyl) relative to the point of attachment to the remainder of the R₂ group, for example:

Suitably, when R₂ is C₁₋₄ alkylene(4-7 membered heterocycloalkyl), such as CH₂-azetidinyl or CH₂CH₂-azetidinyl, the azetidinyl is 1-azetidinyl. Suitably, when R₂ is C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl), such as CH₂O-azetidinyl, the azetidinyl is 3-azetidinyl. For example:

Suitably, when the heterocycloalkyl contains one or more nitrogen atoms, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom(s) may be substituted (such as one nitrogen atom is substituted), for example by C₁₋₄ alkyl, C₁₋₄ haloalkyl, such as CH₂CH₂F, C(O)H, C(O)C₁₋₄ alkyl, C(O)OC₁₋₄ alkyl, such as C(O)OtBu, C(O)OC₁₋₄ alkylene(aryl) such as C(O)OBz, C(O)NHC₁₋₄ alkyl, C(O)NHC₁₋₄ alkylene(aryl) such as C(O)NHBz, an Fmoc group, C(O)C₁₋₄ haloalkyl, C(O)OC₁₋₄ haloalkyl or C(O)NHC₁₋₄ haloalkyl. Suitably, when the heterocycloalkyl contains one or more S atoms, the S atom(s) is substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O)₂). Alternatively, any sulphur atom(s) in the heterocycloalkyl ring is not substituted.

When the one or more nitrogen atoms is substituted by C₁₋₄ alkyl, C₁₋₄ haloalkyl, such as CH₂CH₂F, C(O)H, C(O)C₁₋₄ alkyl, C(O)OC₁₋₄ alkyl, such as C(O)OtBu, C(O)OC₁₋₄ alkylene(aryl) such as C(O)OBz, C(O)NHC₁₋₄ alkyl, C(O)NHC₁₋₄ alkylene(aryl) such as C(O)NHBz, an Fmoc group, C(O)C₁₋₄ haloalkyl, C(O)OC₁₋₄ haloalkyl or C(O)NHC₁₋₄ haloalkyl, these substituents may be present in addition to the optional substituents described above for heterocycloalkyl. The substituents on the nitrogen atom may be referred to or function as protecting groups, which can be added and removed by methods known to the person skilled in the art.

Suitably, the cycloalkyl is substituted by 1, 2 or 3 C₁₋₄ alkyl substituents, such as 1 or 2 e.g. 1 C₁₋₄ alkyl substituent, such as methyl, ethyl and propyl, especially methyl. In one embodiment, the cycloalkyl is not substituted.

Suitably, unless R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkylene(OH), C₁₋₄ alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneO(aryl), OC₁₋₄ alkylene(aryl), C₁₋₄ alkylene(4-7 membered heterocycloalkyl), C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl) or C₁₋₄ alkyleneO(C₃₋₆ alkynyl), then m is 0. More suitably, unless R₂ is H, methyl, CH₂OH, CH₂OMe, CH₂OPh, OCH₂Ph, CH₂O (1-(2-fluoroethyl)azetidin-3-yl, CH₂ (3-fluoroazetidin-1-yl), CH₂CH₂ (3-fluoroazetidin-1-yl) or CH₂OCH₂C≡CH, then m is 0.

Suitably, when m is 0, R₂ is not C₁₋₄ alkenylO (4-7 membered heterocycloalkyl). Suitably, when m is 0, R₂ is not CH₂CH₂ (3-fluoroazetidin-1-yl). Suitably, when R₂ is H and m is 1, R₃ is not fluoro in the 3-position.

When present, in one embodiment each R₃ is independently fluoro or methyl, in particular fluoro.

In one embodiment, m is 1 or 2.

In one preferred embodiment, m is 1 and R₃ is in the 3-position. In another preferred embodiment, m is 1 and R₃ is in the 6-position. In another preferred embodiment, m is 2, one R₃ is in the 3-position, and the other R₃ is in the 6-position. In one embodiment, R₂ is H, m is 1 and R₃ is in the 3-position. In one embodiment, m is 0. In one embodiment, R₂ is H and R₃ is in the 3-position.

References to substituent position are in respect of attachment to the amide moiety, for example:

Examples of suitable substituents include 2-OCH₂Ph; 2-CH₂OPh; 2-CH₂O(cyclobutyl), 2—CH₂OH; 2-CH₂OMe; 2-CH₂O (1-(2-fluoroethyl)azetidin-3-yl); 2-CH₂ (3-fluoroazetidin-1-yl); 2—CH₂CH₂ (3-fluoroazetidin-1-yl); 2-CH₂OCH₂C≡CH; 3-methyl; 3-chloro; 3-fluoro; 3-fluoro-2-methyl; 6-fluoro-2-methyl; 2,6-dimethyl; and 3-fluoro-2,6-dimethyl. In one embodiment, each R₃ is the same. In one embodiment, each R₃ is different.

In one embodiment, A is group (Ab):

In one embodiment, R₄ is H. In a second embodiment, R₄ is C₁₋₄ alkyl, such as methyl. In a third embodiment R₄ is C₁₋₄ alkylene(aryl), such as benzyl. In one preferred embodiment, R₄ is H, methyl or benzyl, in particular methyl or benzyl. Suitably, the aryl is substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from C₁₋₄ alkyl, such as methyl; C₃₋₆ cycloalkyl, such as cyclopropyl; C₁₋₄ alkoxy, such as OMe; C₁₋₄ haloalkyl, such as CF₃; halo, such as chloro or fluoro; CN; OH; NR_(4a)R_(4b); SO₂R_(4c); and NHSO₂R_(4c). Suitably, the aryl is substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from C₁₋₄ alkyl, such as methyl; C₃₋₆ cycloalkyl, such as cyclopropyl; C₁₋₄ alkoxy, such as OMe; C₁₋₄ haloalkyl, such as CF₃; halo, such as chloro or fluoro; and CN. Suitably, the aryl is substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from OH; NR_(4a)R_(4b); SO₂R_(4c); and NHSO₂R_(4c). Suitably, the aryl is substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from methyl, chloro and fluoro. In one embodiment, the aryl is substituted by 1, 2 or 3, such as 1 or 2 e.g. 1 methyl groups. In one embodiment, the aryl is substituted by 1, 2 or 3, such as 1 or 2 e.g. 1 chloro groups. In one embodiment, the aryl is substituted by 1, 2 or 3, such as 1 or 2 e.g. 1 fluoro groups. Suitably, the aryl is not substituted.

In one embodiment, R_(4a) is H. In a second embodiment, R_(4a) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R_(4a) is H or methyl.

In one embodiment, R_(4b) is H. In a second embodiment, R_(4b) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R_(4b) is C₃₋₆ cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl. In a fourth embodiment, R_(4b) is C₁₋₄ alkoxy, such as OMe or OEt, especially OMe. In a fifth embodiment, R_(4b) is C₁₋₄ haloalkyl, such as CF₃. In a sixth embodiment, R_(4b) is aryl, such as phenyl. In a seventh embodiment, R_(4b) is 4-7 membered heterocycloalkyl, such as azetidinyl or oxetanyl. In an eighth embodiment, R_(4b) is H or methyl.

In one embodiment, R_(4c) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a second embodiment, R_(4c) is C₃₋₆ cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl. In a third embodiment, R_(4c) is C₁₋₄ alkoxy, such as OMe or OEt, especially OMe. In a fourth embodiment, R_(4c) is C₁₋₄ haloalkyl, such as CF₃. In a fifth embodiment, R_(4c) is aryl, such as phenyl. In a sixth embodiment, R_(4c) is 4-7 membered heterocycloalkyl, such as azetidinyl or oxetanyl. In a seventh embodiment, R_(4c) is H or methyl.

In one embodiment, R⁵ is H.

When present, in one embodiment each R₆ is independently fluoro or methyl. Suitably, n is 1, 2 or 3, such as 1 or 2 e.g. 1.

In one embodiment, n is 0.

In one embodiment, group A is group (Ac):

In one embodiment, R₇ is methyl, CH₂OH or CH₂OMe.

In one embodiment, o is 2.

Suitably, the stereochemistry of R₇ is trans in respect of bond linking the (Ac) group to the amide moiety, for example having one of the two following stereochemical arrangements:

In one preferred embodiment, A is group (Ad):

In one embodiment, X is a bond or O. Suitably, X is a bond. Suitably, X is O. In a second embodiment, X is CH₂.

In one embodiment, R₈ is halo. In one embodiment, R₈ is C₁₋₄ alkyl. In one embodiment, R₈ is C₁₋₄ alkoxy. In one embodiment, R₃ is OH.

When present, in one embodiment each R₃ is independently methyl, OMe or fluoro. In one embodiment, each R₃ is independently OCH₂-cyclopropyl, OCH₂-oxetanyl, OCH₂CH₂F, methyl, OMe, OEt or fluoro, for example OCH₂CH₂F, OMe or OEt, especially OMe. In another embodiment, each R₃ is independently OCH₂-cyclopropyl, OCH₂-oxetanyl, OCH₂CH₂F or OEt, such as OCH₂-cyclopropyl, OCH₂-oxetanyl or OCH₂CH₂F.

Suitably, the cycloalkyl and heterocycloalkyl present in R₃ are each independently substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from C₁₋₄ alkyl, such as methyl; C₃₋₆ cycloalkyl, such as cyclopropyl; C₁₋₄ alkoxy, such as OMe; C₁₋₄ haloalkyl, such as CF₃; halo, such as chloro or fluoro; CN; OH; NR_(8a)R_(8b); SO₂R_(8c); and NHSO₂R_(8c). Suitably, the cycloalkyl and heterocycloalkyl are each independently substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from C₁₋₄ alkyl, such as methyl; C₃₋₆ cycloalkyl, such as cyclopropyl; C₁₋₄ alkoxy, such as OMe; C₁₋₄ haloalkyl, such as CF₃; halo, such as chloro or fluoro; and CN. Suitably, the cycloalkyl and heterocycloalkyl are each independently substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from OH; NR_(8a)R_(8b); SO₂R_(8c); and NHSO₂R_(8c).

In one embodiment, R_(8a) is H. In a second embodiment, R_(8a) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R_(8a) is H or methyl.

In one embodiment, R_(8b) is H. In a second embodiment, R_(8b) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R_(8b) is C₃₋₆ cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl. In a fourth embodiment, R_(8b) is C₁₋₄ alkoxy, such as OMe or OEt, especially OMe. In a fifth embodiment, R_(8b) is C₁₋₄ haloalkyl, such as CF₃. In a sixth embodiment, R_(8b) is aryl, such as phenyl. In a seventh embodiment, R_(8b) is 4-7 membered heterocycloalkyl, such as azetidinyl or oxetanyl. In an eighth embodiment, R_(8b) is H or methyl.

In one embodiment, R_(8c) is C₁₋₄ alkyl, such as methyl, ethyl or propyl, especially methyl. In a second embodiment, R_(8c) is C₃₋₆ cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl. In a third embodiment, R_(8c) is C₁₋₄ alkoxy, such as OMe or OEt, especially OMe. In a fourth embodiment, R_(8c) is C₁₋₄ haloalkyl, such as CF₃. In a fifth embodiment, R_(8c) is aryl, such as phenyl. In a sixth embodiment, R_(8c) is 4-7 membered heterocycloalkyl, such as azetidinyl or oxetanyl. In a seventh embodiment, R_(8c) is methyl.

Suitably, the cycloalkyl present in R₃ (e.g. cyclopropyl) is substituted by 1, 2 or 3 C₁₋₄ alkyl substituents, such as 1 or 2 e.g. 1 C₁₋₄ alkyl substituent, such as methyl, ethyl and propyl, especially methyl. In one embodiment, the cycloalkyl is not substituted.

Suitably, the heterocycloalkyl present in R₃ (e.g. oxetanyl) is substituted by 1, 2 or 3 substituents, such as 1 or 2 e.g. 1 substituent, each independently selected from fluoro and C₁₋₄ alkyl, such as methyl, ethyl and propyl, especially methyl. In one embodiment, the heterocycloalkyl is not substituted.

Suitably, when the heterocycloalkyl is oxetanyl, the oxygen atom is in the 2- or 3-position (i.e. 2-oxetanyl or 3-oxetanyl) relative to the point of attachment to the remainder of the R₃ group, for example:

Suitably, when R₃ is OC₁₋₄ alkylene(4-7 membered heterocycloalkyl), such as OCH₂-oxetanyl, the oxetanyl is 3-oxetanyl, for example:

When p is 1 or 2, R₈ may be in the 2- and/or 3 position. In one embodiment, p is 1 and R₈ is in the 2-position. In a second embodiment, p is 1 and R₈ is in the 3-position. In a third embodiment, p is 2, one R₃ is in the 2-position and one R₈ is in the 3-position. For example:

Examples of suitable R₈ substituents include 2-methyl, 2-methoxy, 2-ethoxy, 2-OCH₂CH₂F, 2-OCH₂-cyclopropyl and 2-OCH₂-oxetanyl such as 2-methyl and 2-methoxy.

Suitably, when X is a bond, R₈ is not in the 3-position. Suitably, when X is a bond, R₈ is in the 2-position.

Suitable example of substituents are 2-methyl, 2-methoxy and 3-fluoro.

In one embodiment, p is 0 or 1.

Suitably, when X is a bond and p is 0, the compound has the (R) stereochemical configuration. Suitably, when X is as defined above and p is 1, the stereochemistry of R₈ is trans in respect of the bond linking the (Ad) group to the amide substituent, for example having one of the following stereochemical arrangements:

When present, in one embodiment each R₉ is independently fluoro.

Suitably, when q is 1, 2, 3 or 4, R₉ may be in the 5-, 6-, 7- and/or 8-position(s). In one embodiment, q is 1 and R₉ is in the 5-position. In a second embodiment, q is 1 and R₉ is in the 6-position. For example:

Suitably, R₉ is not in the 8-position. Suitably, R₉ is in the 7-position. Suitably, R₉ is in the 6-position. Suitably, R₉ is in the 5-position.

In embodiments wherein X is a bond, it will be understood that the substituent position numbering will change in accordance with the total number of atoms in the bicyclic ring system, for example:

Suitable examples of R₉ substituents when X is a bond are 4-fluoro and 5-fluoro.

In one embodiment, q is 1 or 2.

In one embodiment, D, E and F are C(R₁₀). In a second embodiment, D is N, and E and F are C(R₁₀). In a third embodiment, E is N, and D and F are C(R₁₀). In a fourth embodiment, F is N, and D and E are C(R₁₀).

Suitably, when D and F are C(R₁₀), E cannot be N.

In one embodiment, R₁₀ is H. In a second embodiment, R₁₀ is halo, such as fluoro or chloro, especially chloro. In a third embodiment, R₁₀ is C₁₋₄ alkyl, such as methyl. Suitably each R₁₀ is independently H, fluoro, chloro or methyl.

In one preferred embodiment, the compound of the invention has the formula (Ia):

-   -   wherein A is group (Aa′), (AdI′) or (AdII′);     -   R_(10a) is H, fluoro, chloro or methyl;     -   wherein group (Aa′) is:

-   -   wherein:     -   R_(2d) is methyl, CH₂OMe or CH₂OCH₂C≡CH;     -   each R_(3a) is independently H, methyl or fluoro; and     -   wherein group (AdI′) is:

-   -   wherein:     -   R_(8d) is H, methyl or OMe;     -   R_(9a) is H or F;     -   wherein group (AdII′) is:

-   -   wherein:     -   X is O; and     -   R_(8a′) is methyl;     -   provided that when A is group (AdI′) and one of R_(10a) is         fluoro or chloro, the two remaining R_(10a) groups are         independently H;     -   or a pharmaceutically acceptable salt and/or solvate thereof.

In one embodiment, the compound of formula (I) is selected from the group consisting of:

-   (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; -   (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; -   (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl) acrylamide     (racemic mixture); -   (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl) acrylamide     (enantiomer 1); -   (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl) acrylamide     (enantiomer 2); -   (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; -   (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; -   (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide; -   (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; -   (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide     (mixture of stereoisomers); -   (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide     (stereoisomer 1); -   (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide     (stereoisomer 2); -   (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide     (stereoisomer 3); -   (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide     (stereoisomer 4); -   (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (mixture     of stereoisomers); -   (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide     (stereoisomer 1); -   (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide     (stereoisomer 2); -   (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide     (stereoisomer 3); -   (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide     (stereoisomer 4); -   (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide; -   (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide; -   (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide     (mixture of stereoisomers); -   (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide     (stereoisomer -   1); -   (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide     (stereoisomer -   2); -   (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide; -   (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide     hydrochloride; -   (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; -   (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide; -   (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide; -   (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; -   (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide;     and -   (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide;     -   or a pharmaceutically acceptable salt and/or solvate of any one         thereof.

The definition of the compounds of formula (I) is intended to include all tautomers of said compounds.

The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt and/or solvate thereof. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and/or solvate, such as a pharmaceutically acceptable salt.

It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compounds of formula (I) may be of use in other contexts such as during preparation of the compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid additional salts may be formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.

Certain compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).

It is to be understood that the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an “isotopically enriched variant form”). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (²H or D), carbon-11 (¹¹C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-15 (¹⁵N), oxygen-15 (¹⁵O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), phosphorus-32 (³²P), sulphur-35 (³⁵S), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), fluorine-18 (¹⁸F) iodine-123 (¹²³I), iodine-125 (¹²⁵I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e. ²H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. In one embodiment, the compounds of the invention are provided in a natural isotopic form. In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. ²H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form. Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

In general, the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples, and modifications thereof. In the following schemes, reactive groups can be protected with protecting groups and deprotected according to established techniques well known to the skilled person.

Generic Routes

Generic routes by which compound examples of the invention may be conveniently prepared are summarised below. In the following description, the groups R_(1a), R_(1b), A and B are as defined above for the compound of formula (I), unless otherwise stated.

Compounds of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (III) under palladium-catalyzed cross coupling conditions, using a palladium pre-catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl₂—CH₂Cl₂), in the presence of a base, such as triethylamine, and a suitable solvent, such as dimethylformamide (DMF).

Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (IV) with a compound of formula (V) under amidation conditions, using an amide coupling reagent, such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), in the presence of a base, such as N,N-diisopropylethylamine (DIPEA, also known as Hünig's base), in a suitable solvent, such as DMF.

Compounds of formula (I) may be also be prepared by reacting a compound of formula (VI) with a compound of (V) under basic conditions, using a base such as lithium bis(trimethylsilyl)amide (LiHMDS), in a suitable solvent, such as tetrahydrofuran (THF).

Compounds of formula (II) are commercially available. Compounds of formula (II) may also be prepared by reacting a compound of formula (VII) with a compound of formula (VIII) in the presence of a base, such as N,N-diisopropylethylamine, in a suitable solvent, such as dichloromethane (DCM).

Compounds of formula (VI) may be obtained by reacting a compound of formula (IX) with a compound of formula (III) under palladium-catalyzed cross coupling conditions, using a palladium-precatalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl₂—CH₂Cl₂), in the presence of a base, such as triethylamine, and a suitable solvent, such as dimethylformamide (DMF).

Compounds of formula (IV) may be obtained by reacting a compound of formula (VI) under hydrolysis conditions, using a base, such as sodium hydroxide (NaOH), in a suitable solvent system, such as a mixture of methanol and water.

Compounds of formula (VII), wherein R_(1a) is H, A is group (Aa), R₂ is C₁₋₄ alkyl, m is 2 and R₃ is C₁₋₄ alkyl or halo, may be prepared in two steps. Nitro compounds of formula (XVI) may be reacted under palladium-catalyzed cross coupling conditions, using a palladium-precatalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl₂—CH₂Cl₂), an organoboron compound, such as trimethyl-1,3,5,2,4,6-trioxatriborinane, a base, such as caesium carbonate (Cs₂CO₃), and a suitable solvent system, such as a mixture of water 1,4-dioxane, to give a compound of formula (XVII). The compound of formula (XVII) may be further reacted with a metal, such as iron, in the presence of an acid, such as acetic acid, to give the compound of formula (VII).

Compounds of formula (V) wherein A is group (Ad), X is a bond, q is 0, p is 1 and R₈ is OC₁₋₄ haloalkyl, OC₁₋₄ alkylene(4-7 membered heterocycloalkyl) or C₁₋₄ alkoxy may be prepared by reacting a compound of formula (XXI), wherein PG is a nitrogen protecting group, such as tert-butoxycarbonyl (BOC), with a compound of formula (XXII), wherein C is C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ alkylene(4-7 membered heterocycloalkyl), in the presence of a base e.g. NaH in a suitable solvent e.g. THF, to afford compounds of formula (XXIII). Deprotection of the compounds of formula (XXIII) e.g. with aqueous acid, such as 2 M HCl, in a suitable solvent, such as methanol affords compounds of formula (V).

Compounds of formula (V) wherein A is group (Ad), X is a bond, q is 0, p is 1 and R₃ is OC₁₋₄ alkylene(C₃₋₆ cycloalkyl) may be prepared by treating a compound of formula (XXIV), wherein PG is a nitrogen protecting group, such as tert-butoxycarbonyl (BOC), with a suitable reagent e.g. di-iodomethane, in the presence of an organometallic reagent e.g. ZnEt₂ in a suitable solvent, such as dichloromethane, to afford compounds of formula (XXV). Deprotection of the compounds of formula (XXV) e.g. with aqueous acid, such as 2 M HCl, in a suitable solvent, such as methanol affords compounds of formula (V).

Therefore, in one embodiment the invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, which comprises reacting a compound of formula (II):

wherein A, R_(1a) and R_(1b) are as defined for the compound of formula (I); or salt thereof; with a compound of formula (III):

wherein X is halo, such as bromo or iodo, and B is as defined for the compound of formula (I); or a salt thereof;

provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

The invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, which comprises reacting a compound of formula (IV):

wherein R_(1b) and B are as defined for the compound of formula (I); or a salt thereof; with a compound of formula (V):

wherein A and R_(1a) are as defined for the compound of formula (I); or a salt thereof; provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

The invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, which comprises reacting a compound of formula (VI):

wherein R_(1b) and B are as defined for the compound of formula (I); or a salt thereof; with a compound of formula (V):

wherein A and R_(1a) are as defined for the compound of formula (I); or a salt thereof; provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

Therapeutic Methods

Compounds of formula (I) of the present invention have utility as inhibitors of mPTP.

Therefore, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use a pharmaceutical, in particular in the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use a pharmaceutical, in particular in the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use a pharmaceutical, in particular in the prophylaxis of a disease or disorder in which inhibition of mPTP provides a prophylactic effect, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the prophylaxis of a disease or disorder in which inhibition of mPTP provides a prophylactic effect, for example those diseases and disorders mentioned herein below.

The invention also provides a method of preventing or treating a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The invention also provides a method of treating a disease or disorder in which inhibition of mPTP provides a therapeutic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The invention also provides a method of preventing a disease or disorder in which inhibition of mPTP provides a prophylactic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The term ‘treatment’ or ‘treating’ as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.

The term ‘prophylaxis’ or ‘preventing’ is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.

In one embodiment, the disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia or re-perfusion injury, metabolic diseases, inflammatory or autoimmune diseases, diseases of aging and renal diseases.

In one particular embodiment, the disease or disorder is a degenerative or neurodegenerative disease, such as Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontal temporal dementia, chemotherapy induced neuropathy, Huntington's disease, spinocerebellar ataxias, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury and Friedreich's ataxia. In one preferred embodiment, the disease or disorder is Parkinson's disease. In one preferred embodiment, the disease or disorder is Alzheimer's disease. In one preferred embodiment, the disease or disorder is amyotrophic lateral sclerosis.

In another particular embodiment, the disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorders, schizophrenia and epilepsy.

In another embodiment, the disease or disorder is ischemia or re-perfusion injury, such as acute myocardial infarction, stroke, kidney ischemia reperfusion injury, and organ damage during transplantation.

In another embodiment, the disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes associated conditions, obesity and feeding behaviours, and non-alcoholic fatty liver disease.

In another embodiment, the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis and hepatitis.

In another embodiment, the disease or disorder is a disease of aging, such as bone repair, bone weakness in aging in osteoporosis and sarcopenia.

In another embodiment, the disease or disorder is a renal disease, such as chronic kidney disease associated with APOL1 genetic variants and chronic kidney disease.

The compounds of formula (I) are expected to be useful in the treatment or prophylaxis of a mitochondrial disease.

Therefore, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment of a mitochondrial disease, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment of a mitochondrial disease, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below.

The invention also provides a method of treating or preventing a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The invention also provides a method of treating a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The invention also provides a method of preventing a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

Suitably, the mitochondrial disease is selected from Reye syndrome, Leber's hereditary optic neuropathy and associated disorders and disorders as disclosed in CA2884607A1 (Stealth Peptides International Inc.).

The compounds of formula (I) are expected to be useful in the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration.

Therefore, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below.

The invention also provides a method of treating or preventing a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The invention also provides a method of treating a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

The invention also provides a method of preventing a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below.

Suitably, the disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration is selected from Amyotrophic Lateral Sclerosis, Frontotemporal dementia, Facial onset sensory and motor neuronopathy, Primary lateral sclerosis, Progressive muscular atrophy, Inclusion body myopathy associated with early-onset Paget disease of the bone and Frontotemporal lobar degeneration dementia, Perry disease, Chronic traumatic encephalopathy, Severe traumatic brain injury, Alzheimer's disease, Hippocampal sclerosis dementia, Limbic-predominant age-related TDP-43 encephalopathy, and Cerebral age-related TDP-43 with sclerosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with fibrosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment of a disease or disorder associated with fibrosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis of a disease or disorder associated with fibrosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with fibrosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with fibrosis.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the manufacture of a medicament for the prophylaxis of a disease or disorder associated with fibrosis.

The invention also provides a method of treating or preventing a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.

The invention also provides a method of treating a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof.

The invention also provides a method of preventing a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. Suitably, the disease or disorder associated with fibrosis is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis.

Suitably the subject is a mammal, in particular the subject is a human.

Pharmaceutical Compositions

For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, and a pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below.

In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, for use in the treatment or prophylaxis of a disease or disorder as described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, for use in the treatment of a disease or disorder as described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, for use in the prophylaxis of a disease or disorder as described herein.

In a further embodiment, there is provided a method for the treatment or prophylaxis of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof. In a further embodiment, there is provided a method for the treatment of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof. In a further embodiment, there is provided a method for the prophylaxis of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof.

The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder as described herein. The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) thereof, in the manufacture of a medicament for the treatment of a disease or disorder as described herein. The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) thereof, in the manufacture of a medicament for the prophylaxis of a disease or disorder as described herein.

The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment or prophylaxis, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated or prevented, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, suitably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most suitably 0.1 to 5.0 mg/kg/day, for adult humans. For oral administration, the compositions are suitably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, suitably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most suitable doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, suitably compounds of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), intranasal (also known as nasal administration), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators) insufflation, rectal, intraperitoneal, topical (including dermal, buccal, sublingual, and intraocular) and intrathecal administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

Suitable pharmaceutical formulations according to the invention are those suitable for oral, intrathecal and parenteral administration; and more suitably are those suitable for oral or intrathecal administration.

In one suitable embodiment a compound according to formula (I) is administered by intrathecal administration. Such a method of administration involves injection of the compound of the invention into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid. This is advantageous for the administration of compounds which may not be able to pass the blood brain barrier via other routes of administration, such as oral administration.

Suitable pharmaceutical formulations may be administered intrathecally by continuous infusion such as with a catheter, or a pump, or intrathecally by a single bolus injection or by intermittent bolus injection. To be administered intrathecally, the pharmaceutical composition may be administered continuously or intermittently. The intermittent administration may be, for example, every thirty minutes, every hour, every several hours, every 24 hours, every couple of days (for example every 48 or 72 hours) or any combination thereof.

When the pharmaceutical formulation of the invention is administered continuously, implantable delivery devices, such as an implantable pump may be employed. Examples of such delivery devices include devices which can be implanted subcutaneously in the body or in the cranium, and provides an access port through which the pharmaceutical formulation may be delivered to the nerves or brain.

Intrathecal dosages of the present invention, when used for the indicated effects, will typically be less than 1 mg, such as less than 500 μg, for example less than 250 μg per kg of body weight when administered in a single dose or intermittently for adult humans. When administered continuously, the intrathecal dosages of the present invention will typically be less than 250 μg per kg body weight per hour, such as less than 125 μg per kg body weight per hour for adult humans.

In another suitable embodiment a compound according to formula (I) is administered by intranasal, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators) or insufflation administration. Such a method of administration allows for low doses of the compound of the invention to be administered, which can lead to a reduction in side-effects. For example, a daily dose of 10 to 0.01 μg, suitably 1 to 0.01 μg, and more suitably in the region of as low as 0.1 μg (100 ng) of compound of the invention may be used.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The compounds of formula (I) can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising a compound of the present invention, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The compounds of the invention may also be administered liposomally.

Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating a compound of the present invention with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

The compounds of formula (I) can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1.2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine (cephaline), or phosphatidylcholine (lecithin).

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

Exemplary compositions for intranasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.

Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

Suitable unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

The compounds of formula (I) are expected to display one or more of the following advantageous properties:

-   -   inhibitory activity of mPTP as demonstrated in the assay of         Biological Example 1; and     -   improved solubility and/or improved intrinsic clearance         (CL_(int)) resulting in e.g. improved oral bioavailability         and/or improved systemic exposure as demonstrated in the assays         of Biological Examples 2 and 3.

The invention is further exemplified by the following non-limiting examples.

EXAMPLES

The invention is illustrated by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the invention and are not meant to limit the scope of the invention in any way with respect to compounds or processes. It is understood that, although specific reagents, solvents, temperatures and time periods are used, there are many possible equivalent alternatives that can be used to produce similar results. This invention is meant to include such equivalents.

General Experimental Details

Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Unless otherwise stated, all compounds with chiral centres are racemic. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities, ranging from for example 85% to 99%. Calculations of number of moles and yield are in some cases adjusted for this.

Purity of final compounds was confirmed by HPLC/MS analysis and determined to be at least ≥90%, and in the significant majority of cases ≥95%. Analytical LCMS was conducted using the instrumentation shown in Table 1. ¹H NMR were recorded at 300K in a Bruker 300 MHz instruments (ADVANCE III and ADVANCE III HO). Flash prep HPLC was conducted using the following columns: XBridge Prep C18 OBD Column, 5 um, 19×150 mm; Welch Xtimate C18, 21.2×250 mm, 5 um; SunFire Prep C18 OBD 19×150 mm×5 um. SFC purification was conducted using the following columns; (a) CHIRALPAK AS-H, 3*25 cm, 5 um (b) SFC-YMC Cellulose-SB, 4.6×100 mm, 3 um.

TABLE 1 Analytical LC-MS conditions Instrument ID Column Mobile Phase Flow Rate LCMS01 Halo-C18, A: H₂O/0.05%TFA; B: ACN 1.5 mL/min 30*3.0 mm, 2.0 μm LCMS02 Cortecs C18+, A: H₂O/0.05%TFA; B: ACN/0.05%TFA 1.5 mL/min 50*3.0 mm, 2.7 μm LCMS03 Halo-C18, A: H₂O/0.1%TFA; B: ACN/0.05%FA 1.5 mL/min 30*3.0 mm, 2.0 μm LCMS04 Kinetex XB-C18, A: H₂O/0.01%TFA; B: ACN/0.01%FA 1.5 mL/min 50*3.0 mm, 2.6 μm LCMS05 Poroshell HPH-C18, A: H₂O/5 mM NH₄HCO₃; B: MeOH 1.0 mL/min 50*3.0 mm, 2.7 μm LCMS06 Xbridge C18, A: H₂O/5 mM NH₄HCO₃ + 0.05% 1.2 mL/min 50*3.0 mm, NH₃•H₂O; B: 5%H₂O in ACN 3.5 μm LCMS07 Poroshell HPH-C18, A: H₂O/0.05% NH₃•H₂O; B: ACN 1.2 mL/min 50*3.0 mm, 2.7 μm LCMS08 Halo C18, A: H₂O/0.05%TFA; B: ACN 1.5 mL/min 50*3.0 mm, 2.7 μm LCMS09 Poroshell HPH-C18, A: H₂O/0.05% NH₃•H₂O; B: ACN 1.2 mL/min 50*3.0 mm, 2.7 μm

ABBREVIATIONS

-   -   CH₃CN Acetonitrile     -   Cs₂CO₃ Cesium Carbonate     -   DCM Dichloromethane     -   DIPEA Diisopropylethylamine     -   DMF Dimethylformamide     -   DMT-MM 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium         chloride     -   Et Ethyl     -   Et₃N Triethylamine     -   EtOAc Ethylacetate     -   EtOH Ethyl alcohol     -   HATU         1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium         3-oxid hexafluorophosphate     -   HCl hydrochloric acid     -   heps hepatocytes     -   K₂CO₃ Potassium Carbonate     -   K₃PO₄ Potassium Phosphate     -   LiHMDS Lithium bis(trimethylsilyl)amide     -   Me Methyl     -   MeOH Methanol     -   NaHCO₃ Sodium bicarbonate     -   NaOAc Sodium acetate     -   NaOH Sodium hydroxide     -   NBS N-bromosuccinimide     -   NCS N-chlorosuccinimide     -   NH₄Cl Ammonium chloride     -   PE Petroleum ether     -   Pd(OAc)₂ Palladium(II) Acetate     -   Pd(dppf)Cl₂·CH₂Cl₂         Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex         with dichloromethane     -   Pd(dppf)Cl₂-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)     -   RT room temperature     -   o/n overnight (16 h)     -   TFA Trifluoroacetic acid     -   THF Tetrahydrofuran     -   THP Tetrahydropyran     -   T₃P Propanephosphonic anhydride     -   uL microlitre     -   uM micromolar

Preparation of Comparative Example 1 Comparative Example 1: (E)-N-(2-methyl-3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide

Comparative Example 1 was prepared according to methods described in Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455). Comparative Example 1 may also be prepared using analogous synthetic methods to those described herein for Examples 1 to 40.

Preparation of Examples 1 to 40 Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide

To a stirred solution of 3-fluoro-2-methyl-aniline (1.0 g, 7.991 mmol, 1.00 eq.) and N,N-diisopropylethylamine (3.1 g, 23.972 mmol, 3.00 eq.) in DCM (40 mL) was added acryloyl chloride (0.7 mL, 8.790 mmol, 1.10 eq.) dropwise at 0° C. under an inert atmosphere of nitrogen. The resulting mixture was stirred at 25° C. under an inert atmosphere of nitrogen for 3 h. The resulting mixture was washed with 2×30 mL of water and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:5). This resulted in 1.04 g (73%) of N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=180

Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-2-methyl-aniline (300 mg, 2.12 mmol, 1.00 eq.), DCM (15 mL), Et₃N (1.0 mL, 7.19 mmol, 3.00 eq.). This was followed by the addition of acryloyl chloride (260 mg, 2.88 mmol, 1.20 eq.) dropwise with stirring at 25° C. The resulting solution was stirred for 5 h at 25° C. The resulting mixture was washed with 2×10 ml of water and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/PE (1:5). This resulted in 300 mg (74%) of N-(3-chloro-2-methylphenyl)prop-2-enamide as a light yellow solid. LC-MS (ES, m/z): [M+H]⁺=196

Intermediate 3: (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic Acid

Step 1: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-1H-indazole (19.6 g, 100.00 mmol, 1.00 eq), 3,4-dihydro-2H-pyran (12.6 g, 150.00 mmol, 1.50 eq), TsOH(1.7 g, 10.00 mmol, 0.10 eq), in DCM (200 mL). The resulting solution was stirred overnight at RT. The resulting solution was concentrated. The residue was applied onto a silica gel column with PE/EtOAc (1:0-3:1). This resulted in 23.9 g (85%) of methyl 3-(1H-indazol-6-yl) acrylate as a solid. LC-MS (ES, m/z): [M+H]⁺=281

Step 2: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(1H-indazol-6-yl) acrylate (23.9 g, 85.00 mmol, 1.00 eq), methyl acrylate (10.98 g, 127.50 mmol, 1.50 eq), Et₃N (23.7 mL, 170.00 mmol, 2.00 eq), Pd(dppf)Cl₂ (1.87 g, 2.55 mmol, 0.03 eq) in DMF (200 mL). The resulting solution was stirred for 2 h at 110° C. The resulting solution was cooled to RT and diluted with 300 mL H₂O. The mixture solution was extracted with 3×500 mL EtOAc. The organic layer was concentrated and the residue was applied onto a silica gel column with PE/EtOAc (1:0-3:1). This resulted in 20.20 g (83%) of (E)-methyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate as a solid. LC-MS (ES, m/z): [M+H]⁺=287

Step 3: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (E)-methyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (11.44 g, 40.00 mmol, 1.00 eq) in MeOH/H₂O (80:40 mL). This was added NaOH (3.20 g, 80.00 mmol, 2.00 equiv). The resulting solution was stirred for 6 h at 50° C. The resulting solution was concentrated to remove MeOH. The pH of aqueous phase was adjusted to 4 with AcOH. The solid was collected by filtration. This resulted in 8.16 g (75%) of methyl 3-(1H-indazol-6-yl) acrylate as a yellow solid. LC-MS (ES, m/z): [M+H]⁺=273

Example 1: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide

Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 40.00 mg, 0.22 mmol, 1.00 equiv), DMF (2 mL), 6-bromo-7-methyl-1H-indazole (47.1 mg, 0.22 mmol, 1.00 equiv), Et₃N (0.09 mL, 0.67 mmol, 3.00 equiv) and Pd(dppf)Cl₂·CH₂Cl₂ (9.11 mg, 0.011 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 120° C. The crude product was purified by Prep-HPLC. This resulted in 13 mg (19%) of (2E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=310 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.33 (s, 1H), 9.65 (s, 1H), 8.09 (s, 1H), 7.99 (d, J=15.6 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.51-7.40 (m, 2H), 7.25-7.23 (m, 1H), 7.04-6.96 (m, 2H), 2.65 (s, 3H), 2.18 (s, 3H).

Example 2: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (2E)-3-(1H-indazol-6-yl)prop-2-enoic acid (40 mg, 0.21 mmol, 1.00 equiv), DMF (3 mL), T₃P (88 mg, 0.28 mmol, 1.30 equiv), DIPEA (55 mg, 0.43 mmol, 2.00 equiv), indanamine (31 mg, 0.23 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at 25° C. The mixture was purified by Prep-HPLC. This resulted in 12 mg (19%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=304

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.19 (brs, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.71-7.65 (m, 2H), 7.39-7.29 (m, 1H), 7.29-7.19 (m, 4H), 6.75 (d, J=15.6 Hz, 1H), 5.44-5.42 (m, 1H), 3.05-2.91 (m, 2H), 2.45-2.44 (m, 1H), 1.86-1.83 (m, 1H).

Example 3: (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

Into a 8-mL sealed tube, was placed methyl 3-(1H-indazol-6-yl)prop-2-enoate (110 mg, 0.54 mmol, 1.00 eq), (1R)-2,3-dihydro-1H-inden-1-amine hydrochloride (92 mg, 0.54 mmol, 1.00 eq), THF (2 mL). This was followed by the addition of LiHMDS (3.2 mL, 3.26 mmol, 6.00 eq) at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 10 mL of EtOAc. The reaction was then quenched by the addition of 15 mL of Sat NH₄Cl. The organic layer was washed with 15 ml of water, and concentrated in an oven under reduced pressure. The crude product was purified by Flash-Prep-HPLC. This resulted in 72 mg (43%) of N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=304

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.52 (d, J=8.1 Hz, 1H), 8.08 (s, 1H), 7.77-7.62 (m, 3H), 7.35-7.19 (m, 5H), 6.75 (d, J=15.9 Hz, 1H), 5.47-5.39 (m, 1H), 2.98-2.79 (m, 2H), 2.46-2.41 (m, 1H), 1.89-1.81 (m, 1H)

Example 4: (Racemic) (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide

Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed (2E)-3-(1H-indazol-6-yl)prop-2-enoic acid (30 mg, 0.16 mmol, 1.00 equiv), DCM (4 mL), HATU (79 mg, 0.21 mmol, 1.30 equiv), 2-methylcyclohexan-1-amine (20 mg, 0.18 mmol, 1.10 equiv), DIPEA (41 mg, 0.32 mmol, 2.00 equiv). The resulting solution was stirred for 5 h at 25° C. The reaction was then quenched by the addition of 4 mL of water. The resulting solution was extracted with 5 mL of dichloromethane dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC. This resulted in 10 mg (22%) of (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (trans isomer) as an off-white solid and 10 mg (22%) of (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methylcyclohexyl)acrylamide (cis isomer) as an off-white solid.

(E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (trans isomer) LC-MS (ES, m/z): [M+H]⁺=284

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.19 (brs, 1H), 8.08 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.55 (d, J=15.7 Hz, 1H), 7.34 (dd, J=8.5, 1.5 Hz, 1H), 6.71 (d, J=15.6 Hz, 1H), 3.48-3.34 (m, 1H), 1.83-1.62 (m, 4H), 1.37-1.06 (m, 5H), 0.87 (d, J=6.6 Hz, 3H).

(E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methylcyclohexyl)acrylamide (cis isomer) LC-MS (ES, m/z): [M+H]⁺=284

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.26 (brs, 1H), 8.08 (s, 1H), 7.80-7.74 (m, 2H), 7.56 (s, 1H), 7.36-7.33 (m, 1H), 7.26-7.09 (m, 1H), 6.92 (d, J=15.9 Hz, 1H), 4.15-4.02 (m, 1H), 1.91-1.85 (m, 1H), 1.79-1.30 (m, 8H), 0.85 (d, J=6.6 Hz, 3H).

The 550 mg (E)-3-(1H-indazol-6-yl)-N-(2-methylcyclohexyl)acrylamide from Example 4 was purified by SFC (column: CHIRALPAK IG-3, 100*4.6 mm, 3 um IG30CS-UL011, eluting with hexane (0.1% DEA), EtOH/MeOH). This resulted in 60 mg (11%) of trans-(2E)-3-(1H-indazol-6-yl)-N-[(1S,2S)-2-methylcyclohexyl]prop-2-enamide and 80 mg (15%) of trans-(2E)-3-(1H-indazol-6-yl)-N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide as white solid.

Example 4a: Enantiomer 1; LC-MS (ES, m/z): [M+H]⁺=284

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.19 (brs, 1H), 8.07 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J=15.9 Hz, 1H), 7.35-7.32 (m, 1H), 6.70 (d, J=15.9 Hz, 1H), 3.44-3.32 (m, 1H), 1.83-1.62 (m, 4H), 1.42-0.99 (m, 5H), 0.90-0.80 (m, 3H).

Example 4b: Enantiomer 2; LC-MS (ES, m/z): [M+H]⁺=284

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.19 (brs, 1H), 8.07 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J=15.9 Hz, 1H), 7.35-7.32 (m, 1H), 6.70 (d, J=15.9 Hz, 1H), 3.44-3.32 (m, 1H), 1.83-1.62 (m, 4H), 1.42-0.99 (m, 5H), 0.90-0.80 (m, 3H).

Example 5: (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 100-mL sealed tube, was placed 6-bromo-1H-indazole (3.1 g, 15.80 mmol, 1.00 eq), methyl acrylate (1.5 g, 17.40 mmol, 1.10 eq), Et₃N (19.6 mL, 140.80 mmol, 2.00 eq) and Pd(dppf)Cl₂ (345 mg, 4.70 mmol, 0.03 eq) in DMF (50 mL). The resulting solution was stirred for 2 h at 110° C. The resulting solution was concentrated. The residue was applied onto a silica gel column with THF/hexane (35/65). This resulted in 2.3 g (70%) of methyl 3-(1H-indazol-6-yl) acrylate as a yellow solid.

LC-MS (ES, m/z): [M+H]⁺=203

Step 2: Into a 40-mL sealed tube, was placed 7-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.66 mmol, 2.00 eq), MeOH (15.00 mL) and Hydroxylamine hydrochloride (1.1 g, 15.98 mmol, 3.00 eq). The resulting solution was stirred for 16 h at 60° C. The resulting mixture was concentrated. The crude product was diluted with of EtOAc (30.00 mL) and H₂O (15.00 mL). The organic layer was separated and washed with 20 ml of H₂O and concentrated. This resulted in 810 mg (92%) of 7-fluoro-2,3-dihydroinden-1-one oxime as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=166

Step 3: Into a 50-mL round-bottom flask, was placed 7-fluoro-2,3-dihydroinden-1-one oxime (810.0 mg, 4.90 mmol, 1.00 eq) and MeOH (20.0 mL). This was followed by the addition of Pd/C (104.4 mg). The resulting solution was stirred under an atmospheric pressure of H₂ for 16 h at room temperature. The solid was filtered out and washed with 10 mL of MeOH. The combined solution was concentrated. This resulted in 530 mg (71%) of 7-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=152

Step 4: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 7-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazol-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 eq) and THF (3.00 mL). This was followed by the addition of LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of 15 mL of Sat NH₄Cl. The organic layer was washed with 15 ml of water, and dried in an oven under reduced pressure. The crude product was purified by Flash-Prep-HPLC. This resulted in 18 mg (15%) of (7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=322 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.30 (brs, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.80-7.62 (m, 3H), 7.35-7.27 (m, 2H), 7.15-6.97 (m, 2H), 6.67 (d, J=15.9 Hz, 1H), 5.64-5.57 (m, 1H), 3.10-2.88 (m, 2H), 2.49-2.42 (m, 1H), 1.95-1.88 (m, 1H).

Example 6: (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 40-mL sealed tube, was placed 6-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.656 mmol, 2.00 eq), MeOH (15.0 mL) and Hydroxylamine hydrochloride (1.1 g, 15.98 mmol, 3.00 eq). The resulting solution was stirred for 16 h at 60° C. The resulting mixture was concentrated. The crude product was diluted with of EtOAc (30.0 mL) and H₂O (15.0 mL). The organic phase was washed with 20 ml of H₂O. The solid was dried in an oven under reduced pressure. This resulted in 810 mg (92%) of N-[6-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=166

Step 2: Into a 50-mL round-bottom flask, was placed N-[6-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine (810.0 mg, 4.90 mmol, 1.00 eq), MeOH (20.0 mL). This was followed by the addition of Pd/C (104.4 mg, 0.98 mmol, 0.20 eq). The resulting solution was stirred under an atmospheric pressure of H₂ for 16 h at room temperature. The solids were filtered out and washed with 10 mL of MeOH. The combined solution was concentrated. This resulted in 530 mg (71%) of 6-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=152

Step 3: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazol-6-yl)prop-2-enoate (Example 5, Step 1, 73.6 mg, 0.36 mmol, 1.00 eq) and THF (3.0 mL). This was followed by the addition of LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of 15 mL of Sat. NH₄Cl. The organic layer was washed with 15 ml of water, and dried in an oven under reduced pressure. The crude product was purified by Flash-Prep-HPLC. This resulted in 15 mg (13%) of (6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC MS: (ES, m/z): [M+H]⁺=322 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (brs, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.08 (s, 1H), 7.80-7.63 (m, 3H), 7.36-7.27 (m, 2H), 7.08-7.01 (m, 2H), 6.74 (d, J=15.6 Hz, 1H), 5.45-5.37 (m, 1H), 2.98-2.76 (m, 2H), 2.55-2.44 (m, 1H), 1.95-1.87 (m, 1H).

Example 7: (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 40-mL sealed tube, was placed 5-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.66 mmol, 2.00 eq), MeOH (15.0 mL) and Hydroxylamine hydrochloride (1.11 g, 15.98 mmol, 3.00 eq). The resulting solution was stirred for 16 h at 60° C. The resulting mixture was concentrated. The crude product was diluted with of EtOAc (30.0 mL) and H₂O (15.0 mL). The organic layer was separated and washed with 20 ml of H₂O and concentrated. This resulted in 810 mg (92%) of 5-fluoro-2,3-dihydroinden-1-one oxime as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=166

Step 2: Into a 50-mL round-bottom flask, was placed 5-fluoro-2,3-dihydroinden-1-one oxime (810.0 mg, 4.90 mmol, 1.00 eq), MeOH (20.0 mL). This was followed by the addition of Pd/C (104.38 mg). The resulting solution was stirred under H₂ for 16 h at room temperature. The solid was filtered out and washed with 10 mL of MeOH. The combined solution was concentrated. This resulted in 530 mg (71%) of 5-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=152

Step 3: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 5-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazol-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 eq), THF (3.00 mL). This was followed by the addition of LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of 15 mL of Sat. NH₄Cl. The organic layer was washed with 15 ml of water, and dried in an oven under reduced pressure. The crude product was purified by Flash-Prep-HPLC. This resulted in 13 mg (12%) of (5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS: (ES, m/z): [M+H]⁺=322 ¹H NMR: (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.50 (d, J=8.1 Hz, 1H), 8.08 (s, 1H), 7.80-7.62 (m, 3H), 7.35-7.24 (m, 2H), 7.12-6.98 (m, 2H), 6.74 (d, J=15.6 Hz, 1H), 5.39-5.37 (m, 1H), 2.98-2.85 (m, 2H), 2.54-2.46 (m, 1H), 1.92-1.81 (m, 1H).

Example 8: (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 40-mL sealed tube, was placed 4-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.66 mmol, 2.00 eq), MeOH (15.0 mL), and Hydroxylamine hydrochloride (1.11 g, 15.98 mmol, 3.00 eq). The resulting solution was stirred for 16 h at 60° C. The resulting mixture was concentrated. The crude product was diluted with of EtOAc (30.00 mL) and H₂O (15.00 mL). The organic layer was separated and washed with 20 ml of H₂O and concentrated. This resulted in 810 mg (92%) of 4-fluoro-2,3-dihydroinden-1-one oxime as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=166

Step 2: Into a 50-mL round-bottom flask, was placed 4-fluoro-2,3-dihydroinden-1-one oxime (810.0 mg, 4.90 mmol, 1.00 eq), MeOH (20.0 mL). This was followed by the addition of Pd/C (104.38 mg). The resulting solution was stirred for under H₂ for 16 h at room temperature. The solid was filtered out and washed with 10 mL of MeOH. The combined solution was concentrated. This resulted in 530 mg (71%) of 4-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=152

Step 3: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 4-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazol-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 eq), THF (3.00 mL). This was followed by the addition of LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of 15 mL of Sat. NH₄Cl. The organic layer was washed with 15 ml of water, and dried in an oven under reduced pressure. The crude product was purified by Flash-Prep-HPLC. This resulted in 19 mg (16%) of (4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS: (ES, m/z): [M+H]⁺=322 ¹H NMR: (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.54 (d, J=8.1 Hz, 1H), 8.08 (s, 1H), 7.80-7.62 (m, 3H), 7.35-7.24 (m, 2H), 7.12-6.98 (m, 2H), 6.74 (d, J=15.9 Hz, 1H), 5.39-5.37 (m, 1H), 2.98-2.85 (m, 2H), 2.54-2.46 (m, 1H), 1.92-1.81 (m, 1H).

Example 9: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide

Step 1: Into a 500-mL 3-necked round-bottom flask, acryloyl chloride (6.80 g, 75.08 mmol, 1.0 equiv), was added to indanamine (10.0 g, 75.08 mmol, 1.0 equiv) and Et₃N (20.9 mL, 150.16 mmol, 2.0 equiv) in DCM (200.0 mL) at 0° C. The resulting solution was stirred for 15 h at 25° C. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 2×100 mL of dichloromethane and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE(10/1, resulting in 7.3 g (52%) of N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=188

Step 2: Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-7-fluoro-1H-indazole (137.8 mg, 0.64 mmol, 1.2 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4 mL), Et₃N (0.22 mL, 1.60 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120° C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 67 mg (39%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)prop-2-enamide as a off-white solid. LC-MS (ES, m/z): [M+H]⁺=322

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.80 (brs, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.20 (s, 1H), 7.75 (d, J=15.9 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.34-7.18 (m, 5H), 6.85 (d, J=15.9 Hz, 1H), 5.47-5.39 (m, 1H), 3.03-2.94 (m, 1H), 2.90-2.80 (m, 1H), 2.47-2.41 (m, 1H), 1.91-1.79 (m, 1H).

Example 10: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide

Into a 8-mL round-bottom flask, was placed 6-bromo-5-fluoro-1H-indazole (100.00 mg, 0.46 mmol, 1.00 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 87.08 mg, 0.46 mmol, 1.00 equiv), Pd(dppf)Cl₂ (34.03 mg, 0.046 mmol, 0.1 equiv), Et₃N (141.2 mg, 1.39 mmol, 3.00 equiv) and DMF (3.00 mL). The resulting solution was stirred for 15 hr at 120° C. in an oil bath. The mixture was cooled to RT and applied onto a silica gel column with THF/PE (1/1). This resulted in 80 mg (54%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=322 ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 13.32 (s, 1H), 8.61 (d, J=8.1 Hz, 1H), 8.09 (s, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.71-7.62 (m, 2H), 7.30-7.21 (m, 4H), 6.86 (d, J=15.9 Hz, 1H), 5.45-5.42 (m, 1H), 2.98-2.85 (m, 2H), 2.52-2.46 (m, 1H), 1.89-1.82 (m, 1H).

Example 11: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide

Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-4-fluoro-1H-indazole (137.8 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (87.2 mg, 0.11 mmol, 0.2 equiv), DMF (4.0 mL), Et₃N (0.22 mL, 1.60 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120° C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 63.6 mg (37%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=322 ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 13.57 (brs, 1H), 8.50 (d, J=8.1 Hz, 1H), 8.19 (s, 1H), 7.67-7.60 (m, 2H), 7.30-7.20 (m, 4H), 7.09 (d, J=11.7 Hz, 1H), 6.75 (d, J=15.9 Hz, 1H), 5.46-5.38 (m, 1H), 3.03-2.94 (m, 1H), 2.90-2.82 (m, 1H), 2.53-2.40 (m, 1H), 1.91-1.78 (m, 1H).

Example 12: (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-5-chloro-1H-indazole (148.4 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (43.6 mg, 0.05 mmol, 0.10 equiv), DMF(4.0 mL), Et₃N (0.22 mL, 1.60 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120° C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 38.4 mg (21%) of (2E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=338 ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 13.37 (brs, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.94-7.83 (m, 2H), 7.30-7.19 (m, 4H), 6.78 (d, J=15.6 Hz, 1H), 5.47-5.39 (m, 1H), 3.04-2.94 (m, 1H), 2.91-2.80 (m, 1H), 2.46-2.42 (m, 1H), 1.92-1.79 (m, 1H).

Example 13: (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-4-chloro-1H-indazole (148.4 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (43.6 mg, 0.053 mmol, 0.10 equiv), DMF(4.0 mL), Et₃N(0.22 mL, 1.60 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120° C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 57.2 mg (32%) of (2E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=338

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.53 (brs, 1H), 8.47 (d, J=8.1 Hz, 1H), 8.14 (s, 1H), 7.73 (s, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.41 (s, 1H), 7.30-7.18 (m, 4H), 6.79 (d, J=15.6 Hz, 1H), 5.46-5.38 (m, 1H), 3.03-2.94 (m, 1H), 2.90-2.79 (m, 1H), 2.47-2.41 (m, 1H), 1.90-1.79 (m, 1H).

Example 14: (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (Mixture of Stereoisomers)

Step 1: Into a 100-mL round-bottom flask, was placed 2-methyl-2,3-dihydroinden-1-one (2.00 g, 13.68 mmol, 1.00 equiv), NH₂OH·HCl (0.95 g, 13.68 mmol, 1.00 equiv), Et₃N (5.7 mL, 41.04 mmol, 3.00 equiv), MeOH (30.00 mL). The resulting solution was stirred for 15 h at 70° C. in an oil bath. The reaction mixture was cooled to RT. The resulting mixture was concentrated. The residue was applied onto a silica gel column with EtOAc/hexane (1/1). This resulted in 1.8 g (82%) of N-[(1Z)-2-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine as a solid.

LC-MS (ES, m/z): [M+H]⁺=162

Step 2: Into a 100-mL round-bottom flask, was placed N-[(1Z)-2-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine (1.8 g, 11.166 mmol, 1.00 equiv) and Pd/C (0.59 g) in 4 M HCl in MeOH (20.00 mL) and MeOH (50.00 mL) The resulting solution was stirred for 15 h at 20° C. under H₂ (30 Psi). The solution was filtered out and the organic layer was concentrated. This resulted in 1.5 g (73.14%) of 2-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride as a solid.

LC-MS-PH-NRG0310-2 (ES, m/z): [M+H]⁺=148

Step 3: Into a 8-mL round-bottom flask, was placed (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (Example 5, Step 1, 100.0 mg, 0.35 mmol, 1.00 equiv), 2-methyl-2,3-dihydro-1H-inden-1-amine (51.42 mg, 0.35 mmol, 1.00 equiv) and THF (2.0 mL). LiHMDS (1.1 mL, 1.05 mmol, 3.00 equiv) was added and the resulting solution stirred for 1 h at 0° C. in a water/ice bath. The reaction was quenched with 1 mL NH₄Cl and extracted with 2×5 mL EtOAc, and the organic layer was concentrated. This resulted in 100 mg (crude) of (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide as a solid. LC-MS (ES, m/z): [M+H]⁺=402

Step 4: Into a 8-mL vial, was placed (2E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.0 mg, crude) in 4 M HCl in MeOH (1.0 mL) and MeOH (1.0 mL). The mixture was stirred for 15 hr at 20° C. The mixture was concentrated and the crude mixture was purified by Flash-Prep-HPLC. This resulted in 6.5 mg of (2E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=318 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.22 (brs, 1H), 8.47-8.25 (m, 1H), 8.08 (s, 1H), 7.86-7.56 (m, 3H), 7.40-7.14 (m, 5H), 6.89-6.75 (m, 1H), 5.47-4.98 (m, 1H), 3.13-2.95 (m, 1H), 2.78-2.54 (m, 1H), 2.34-2.24 (m, 1H), 1.22-0.92 (m, 3H)

Examples 14a, 14b, 14c, 14d

Separation of (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide by SFC (Column; IG 100×4.6 mm 3.0 um; solvent: MeOH (20 mM NH3)) gave 4 individual isomers.

Example 14a: (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (Stereoisomer 1)

LC-MS (ES, m/z): [M+H]⁺=318

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.16 (s, 1H), 7.80-7.45 (m, 3H), 7.45-7.24 (m, 5H), 6.84 (d, J=15.9 Hz, 1H), 5.45-5.39 (m, 1H), 3.06-2.99 (m, 1H), 2.75-2.60 (m, 2H), 0.93 (d, J=6.6 Hz, 3H)

Example 14b: (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (Stereoisomer 2)

LC-MS (ES, m/z): [M+H]⁺=318

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.16 (s, 1H), 7.80-7.45 (m, 3H), 7.45-7.24 (m, 5H), 6.84 (d, J=15.9 Hz, 1H), 5.45-5.39 (m, 1H), 3.06-2.99 (m, 1H), 2.75-2.60 (m, 2H), 0.93 (d, J=6.6 Hz, 3H)

Example 14c: (E)-3-(1H-indazol-6-yl)-N-((1R,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (Stereoisomer 3)

LC-MS (ES, m/z): [M+H]⁺=318

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.22 (s, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.09 (s, 1H), 7.81-7.65 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.22-7.16 (m, 4H), 6.79 (d, J=15.6 Hz, 1H), 5.07-5.02 (m, 1H), 3.18-3.08 (m, 1H), 2.56-2.51 (m, 1H), 2.34-2.29 (m, 1H), 1.21 (d, J=6.6 Hz, 3H)

Example 14d: (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (Stereoisomer 4)

LC-MS (ES, m/z): [M+H]⁺=318

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.22 (s, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.09 (s, 1H), 7.81-7.65 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.22-7.16 (m, 4H), 6.79 (d, J=15.6 Hz, 1H), 5.07-5.02 (m, 1H), 3.18-3.08 (m, 1H), 2.56-2.51 (m, 1H), 2.34-2.29 (m, 1H), 1.21 (d, J=6.6 Hz, 3H)

Example 15: (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (Mixture of Stereoisomers)

Step 1: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.0 g, 101.24 mmol, 1.00 equiv) and THF (200.0 mL). This was followed by the addition of LiHMDS (121.5 mL, 121.48 mmol, 1.20 equiv) dropwise with stirring at −78° C. The resulting solution was stirred for 40 min at −78° C. To this was added a solution of Mel (17.2 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 25° C. The reaction was then quenched by the addition of 150 mL of Sat. NH₄Cl. The resulting solution was extracted with 2×150 mL of EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30%) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as light yellow oil.

Step 2: Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 3-methyl-2,3-dihydro-1-benzopyran-4-one (1.1 g, 6.78 mmol, 1.00 equiv), MeOH (20.0 mL), NH₂OH·HCl (1.4 g, 20.35 mmol, 3.00 equiv), Et₃N (2.8 mL, 20.35 mmol, 3.00 equiv). The resulting solution was stirred for 15 h at 70° C. The resulting mixture was concentrated. The residue was diluted with 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The resulting mixture was concentrated. This resulted in 1 g (83%) of N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine as a white solid.

Step 3: Into a 100-mL vial purged and maintained with an inert atmosphere of H₂, was placed N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine (0.70 g, 3.95 mmol, 1.00 equiv), MeOH (20.00 mL), Pd/C (0.06 g). The resulting solution was stirred for 12 h at 40° C. The solids were filtered out. The resulting mixture was concentrated. This resulted in 530 mg (82%) of 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine as light yellow oil.

Step 4: Into a 8-mL sealed tube, was placed methyl 3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 150 mg, 0.52 mmol, 1.00 eq), 7-methyl-2,3-dihydro-1H-inden-1-amine (154.3 mg, 1.04 mmol, 2.00 eq), THF (3.0 mL). This was followed by the addition of LiHMDS (2.1 mL, 2.09 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 0.5 h at room temperature. The reaction was then quenched by the addition of 2 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried by Na₂SO₄ and concentrated. This resulted in 130 mg (crude) of N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=418

Step 5: Into a 40-mL sealed tube, was placed N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (130 mg, crude), MeOH (4.0 mL), 4 M HCl/MeOH (4.00 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 19 mg of 3-(1H-indazol-6-yl)-N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=334

¹H NMR (300 MHz, CD₃OD, ppm): δ 8.07 (s, 1H), 7.81-7.70 (m, 3H), 7.47-7.43 (m, 1H), 7.22-7.14 (m, 2H), 6.93-6.74 (m, 3H), 5.32-4.92 (m, 1H), 4.28-4.14 (m, 1H), 4.00-3.31 (m, 1H), 2.38-2.19 (m, 1H), 1.10-1.03 (m, 3H).

Examples 15a, 15b, 15c, 15d

Separation of (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide by SFC (Column; SB 100×4.6 mm 3.0 um; solvent: MeOH (20 mM NH3)) gave 4 individual isomers.

Examples 15a (Stereoisomer 1)

LC-MS (ES, m/z): [M+H]⁺=334

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.36 (d, J=9.3 Hz, 1H), 8.07 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.70-7.63 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 2H), 6.92-6.87 (m, 1H), 6.84-6.77 (m, 2H), 5.25-5.20 (m, 1H), 4.15-4.10 (m, 1H), 3.95-3.88 (m, 1H), 2.29-2.28 (m, 1H), 0.91 (d, J=6.9 Hz, 3H).

Examples 15b (Stereoisomer 2)

(ES, m/z): [M+H]⁺=334

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.36 (d, J=9.3 Hz, 1H), 8.07 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.70-7.63 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 2H), 6.92-6.87 (m, 1H), 6.84-6.77 (m, 2H), 5.25-5.20 (m, 1H), 4.15-4.10 (m, 1H), 3.95-3.88 (m, 1H), 2.29-2.28 (m, 1H), 0.91 (d, J=6.9 Hz, 3H).

Examples 15c (Stereoisomer 3)

LC-MS): [M+H]⁺=334

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.22 (s, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.72-7.66 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.19-7.13 (m, 2H), 6.92-6.87 (m, 1H), 6.82-6.74 (m, 2H), 4.87-4.82 (m, 1H), 4.25-4.20 (m, 1H), 3.99-3.92 (m, 1H), 2.51-2.50 (m, 1H), 0.95 (d, J=6.9 Hz, 3H).

Examples 15d (Stereoisomer 4)

LC-MS-PH-NRG0375-0 (ES, m/z): [M+H]⁺=334

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.22 (s, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.72-7.66 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.19-7.13 (m, 2H), 6.92-6.87 (m, 1H), 6.82-6.74 (m, 2H), 4.87-4.82 (m, 1H), 4.25-4.20 (m, 1H), 3.99-3.92 (m, 1H), 2.51-2.50 (m, 1H), 0.95 (d, J=6.9 Hz, 3H).

Example 16: (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 330.0 mg, 1.15 mmol, 1.00 equiv), THF (20.0 mL), 2-(benzyloxy)aniline (298.5 mg, 1.50 mmol, 1.30 equiv). This was followed by the addition of LiHMDS (3.5 ml, 1 M in THF, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 10 mL NH₄Cl. The resulting solution was extracted with 2×30 mL of EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated. This resulted in 310 mg (curde) of (2E)-N-[2-(benzyloxy)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a light yellow solid.

Step 2: Into a 50-mL 3-necked round-bottom flask, was placed (2E)-N-[2-(benzyloxy)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.0 mg, crude). HCl in MeOH (4 M, 10.00 mL) was introduced in at 25° C. The resulting solution was stirred for 30 min at 40° C. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC. This resulted in 20 mg of (2E)-N-[2-(benzyloxy)phenyl]-3-(1H-indazol-6-yl)prop-2-enamide as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=370

¹H NMR (300 MHz, DMSO-d₆, ppm): 13.26 (s, 1H), 9.36 (s, 1H), 7.13-7.10 (m, 2H), 7.83-7.70 (m, 3H), 7.54-7.52 (m, 2H), 7.46-7.42 (m, 3H), 7.39-7.24 (m, 2H), 7.11-7.05 (m, 2H), 6.97-6.94 (m, 1H), 5.28 (s, 2H).

Example 17: (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide

Step 1: Into a 20-mL sealed tube, was placed methyl 3-(1H-indazol-6-yl) acrylate (Intermediate 3, 150.0 mg, 0.55 mmol, 1.00 eq), 2-(phenoxymethyl)aniline (109.8 mg, 0.55 mmol, 1.00 eq), MeOH (5.0 mL) and DMT-MM (228.7 mg, 0.83 mmol, 1.50 eq). The resulting solution was stirred for 16 h at room temperature. Water (6.00 mL) was drop wised under stirring. The solids were collected by filtration. This resulted in 130 mg (52%) of 3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-(phenoxymethyl)phenyl]prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=454

Step 2: Into a 20-mL sealed tube, was placed (E)-N-(2-(phenoxymethyl)phenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (50.0 mg, 0.11 mmol, 1.00 eq), MeOH (4.0 mL), HCl/MeOH (4.0 mL, 4 M). The resulting solution was stirred for 5 h at room temperature and concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 29 mg (71%) of 3-(1H-indazol-6-yl)-N-[2-(phenoxymethyl)phenyl]prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=370

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.26 (s, 1H), 9.72 (s, 1H), 8.10 (s, 1H), 7.83-7.50 (m, 4H), 7.41-7.21 (m, 10H), 5.16 (s, 2H).

Example 18: (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed cyclobutanol (1.0 g, 13.86 mmol, 1.00 eq), 3,3,3-trichloropropenenitrile (2.2 g, 13.86 mmol, 1.00 eq), DCM (20.0 mL). This was followed by the addition of DBU (0.21 g, 1.38 mmol, 0.10 eq) at 0° C. The resulting solution was stirred for 1 h at 0-5° C. The resulting mixture was concentrated under low temp. The residue was applied onto a silica gel column with EtOAc/PE(5:95). This resulted in 1.3 g (43%) of cyclobutyl-2,2,2-trichloroethanimidoate as light pink oil. LC-MS (ES, m/z): [M+H]⁺=216

Step 2: Into a 50-mL 3-necked round-bottom flask, was placed 2-nitrobenzyl alcohol (679.1 mg, 3.69 mmol, 1.20 eq), DCM (20.01 mL). This was followed by the addition of cyclobutyl 2,2,2-trichloroethanimidoate (800.0 mg, 3.69 mmol, 1.00 eq) at 0° C. After stirring for 10 min at 0° C., BF₃·Et₂O (472.0 mg, 3.33 mmol, 0.90 eq) was added. The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under low temp. The residue was applied onto a silica gel column with THF:PE=5:95. This resulted in 530 mg (69%) of 1-(cyclobutoxymethyl)-2-nitrobenzene as a light pink solid.

Step 3: Into a 40-mL sealed tube, was placed 1-(cyclobutoxymethyl)-2-nitrobenzene (500.0 mg, 2.41 mmol, 1.00 eq), MeOH (10.0 mL), H₂O (2.0 mL), Zn (789.1 mg, 2.06 mmol, 5.00 eq), NH₄Cl (1.3 g, 24.13 mmol, 10.00 eq). The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The filtrate was concentrated. The residue was diluted with 50 mL of EtOAc. The resulting mixture was washed with 20 ml of H₂O. The organic phase was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 160 mg (37%) of 2-(cyclobutoxymethyl)aniline as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=178

Step 4: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (60.0 mg, 0.21 mmol, 1.00 eq), 2-(cyclobutoxymethyl)aniline (37.1 mg, 0.21 mmol, 1.00 eq) and THF (4.00 mL). This was followed by the addition of LiHMDS (0.63 mL, 0.63 mmol, 3.00 eq, 1 M in THF) at 0° C. The resulting solution was stirred for 0.5 h at room temperature. The reaction mixture was quenched by the addition of 10 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried by Na₂SO₄, and concentrated. This resulted in 83 mg (crude) of N-[2-(cyclobutoxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=432

Step 5: Into a 8-mL sealed tube, was placed (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (83.00 mg, crude), DCM (2.00 mL), TFA (2.00 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 18 mg of N-[2-(cyclobutoxymethyl)phenyl]-3-(1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=348

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.27 (s, 1H), 9.51 (s, 1H), 8.11 (s, 1H), 7.84-7.64 (m, 4H), 7.46-7.40 (m, 2H), 7.34-7.17 (m, 2H), 6.98 (d, J=15.6 Hz, 1H), 4.44 (s, 2H), 4.02-3.97 (m, 1H), 2.18-2.10 (m, 2H), 1.92-1.86 (m, 2H), 1.65-1.61 (m, 1H), 1.49-1.43 (m, 1H).

Example 19: (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 100-mL round-bottom flask, was placed 7-nitroindazole (3.0 g, 18.39 mmol, 1.00 eq), K₂CO₃ (7.6 g, 55.17 mmol, 3.00 eq), CH₃CN (50.0 mL), PhCH₂Br (4.7 g, 27.58 mmol, 1.50 eq). The resulting solution was stirred for 16 h at room temperature. The resulting solution was poured into 150 mL of water. The solids were collected by filtration. The residue was applied onto a silica gel column. This resulted in 1.60 g (34%) of 1-benzyl-7-nitroindazole as a red solid and 1.40 g (30%) of 2-benzyl-7-nitroindazole as a red solid.

Step 2: Into a 50-mL round-bottom flask, was placed 1-benzyl-7-nitroindazole (820.0 mg, 3.24 mmol, 1.00 eq), Zn (1.1 g, 16.19 mmol, 5.00 eq), NH₄Cl (1.7 g, 32.38 mmol, 10.00 eq), MeOH (30.0 mL), H₂O (5.0 mL). The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The resulting solution was concentrated. The residue was diluted with 50 mL of EtOAc. The resulting mixture was washed with 20 ml of H₂O and 20 mL of brine. The organic phase was concentrated. This resulted in 650 mg (89%) of 1-benzylimidazol-7-amine as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=224

Step 3: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 equiv), THF (3.00 mL) and 1-benzylimidazol-7-amine (175.5 mg, 0.78 mmol, 1.50 equiv). This was followed by the addition of LiHMDS (2.10 mL, 2.10 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 0.5 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried with sodium sulfate, and concentrated. This resulted in 120 mg (crude) of N-(1-benzylimidazol-7-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=478

Step 4: Into a 20-mL sealed tube, was placed (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (120.0 mg, crude), MeOH (4.0 mL), 4 M HCl/MeOH (4.0 mL). The resulting solution was stirred for 5 h at room temperature and the resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 17 mg of N-(1-benzylimidazol-7-yl)-3-(1H-indazol-6-yl)prop-2-enamide as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=394

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.27 (brs, 1H), 10.15 (brs, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.85-7.63 (m, 4H), 7.56-7.43 (m, 1H), 7.34-7.11 (m, 5H), 6.97-6.56 (m, 3H), 5.81 (s, 2H).

Example 20: (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide

Step 1: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (220.0 mg, 0.77 mmol, 1.00 equiv), THF (20.0 mL), 1-methylindazol-7-amine (147.0 mg, 1.00 mmol, 1.30 equiv) and LiHMDS (2.3 mL, 2.31 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 100 mL of EtOAc, dried over anhydrous sodium sulfate and concentrated. This resulted in 220 mg (crude) of (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide as a solid.

Step 2: Into a 50-mL 3-necked round-bottom flask, was placed (2E)-(1-(tetrahydro-2H-pyran-2-yl)-N-(1-methylindazol-7-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (80.00 mg, crude). To the above 4 M HCl/MeOH (10.00 mL) was introduced in at 25° C. The resulting solution was stirred for 30 min at 40° C. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC. This resulted in 20 mg of (2E)-3-(1H-indazol-6-yl)-N-(1-methylindazol-7-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=318 ¹H-NMR (300 MHz, DMSO-d₆, ppm): 13.27 (s, 1H), 10.16 (s, 1H), 8.12-8.08 (m, 2H), 7.85-7.77 (m, 3H), 7.70-7.68 (m, 1H), 7.48-7.45 (m, 1H), 7.26-7.24 (m, 1H), 7.16-7.11 (m, 1H), 7.02 (d, J=15.9 Hz, 1H), 4.12 (s, 3H).

Example 21: (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide

Step 1: Into an 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 eq), m-toluidine (84.2 mg, 0.78 mmol, 1.50 eq), THF (3.00 mL) and LiHMDS (2.1 mL, 2.09 mmol, 4.00 eq, 1 M in THF). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This resulted in 130 mg (crude) of (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(m-tolyl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=362

Step 2: Into an 8-mL sealed tube, was placed (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(m-tolyl)acrylamide (130.00 mg, crude), MeOH (2.00 mL), HCl/MeOH (2.00 mL, 4 M). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under low temperature. The crude product was purified by Flash-Prep-HPLC. This resulted in 35 mg of (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=278

¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 10.12 (s, 1H), 8.11 (s, 1H), 7.83-7.70 (m, 3H), 7.50-7.39 (m, 3H), 7.26-7.20 (m, 1H), 7.09-6.88 (m, 2H), 2.27 (s, 3H).

Example 22: (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 130.0 mg, 0.45 mmol, 1.00 eq), 3-chloroaniline (86.9 mg, 0.68 mmol, 1.50 eq), THF (3.0 mL) and LiHMDS (1.8 mL, 1.82 mmol, 4.00 eq, 1 M in THF). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried by Na₂SO₄, and concentrated. This resulted in 135 mg (crude) of N-(3-chlorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS-PH-NRG0319-1 (ES, m/z): [M+H]⁺=382

Step 2: Into a 8-mL sealed tube, was placed (N-(3-chlorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (130 mg, crude), MeOH (2.00 mL), 4 M HCl/MeOH (2.00 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 42 mg of (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=298

¹HNMR (300 MHz, DMSO-d₆, ppm): δ 13.35 (brs, 1H), 10.4 (s, 1H), 8.11 (s, 1H), 7.97-7.74 (m, 4H), 7.56-7.53 (m, 1H), 7.43-7.35 (m, 2H), 7.15-7.12 (m, 1H), 6.90 (d, J=15.9 Hz, 1H).

Example 23: (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (150.0 mg, 0.52 mmol, 1.00 eq), 3-fluoroaniline (87.3 mg, 0.78 mmol, 1.50 eq), THF (3.0 mL), LiHMDS (2.1 mL, 2.10 mmol, 4.00 eq). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried with sodium sulfate and concentrated. This resulted in 128 mg (crude) of N-(3-fluorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=366

Step 2: Into a 8-mL sealed tube, was placed N-(3-fluorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (120.0 mg, crude), MeOH (2.0 mL), 4 M HCl/MeOH (2.0 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 33 mg of (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=282

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.30 (brs, 1H), 10.43 (s, 1H), 8.11 (s, 1H), 7.84-7.73 (m, 4H), 7.47-7.10 (m, 3H), 6.96-6.87 (m, 2H).

Example 24: (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dimethylaniline (160.0 mg, 1.32 mmol, 1.00 equiv), DCM (10.0 mL), triethylamine (0.55 mL, 3.96 mmol, 3.00 equiv). This was followed by the addition of acryloyl chloride (143.40 mg, 1.58 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at 25° C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane. The organic layer dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/3). This resulted in 150 mg (65%) of N-(2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=176

Step 2: Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(2,6-dimethylphenyl)prop-2-enamide (50.0 mg, 0.29 mmol, 1.00 equiv), DMF (4.0 mL), 6-bromo-1H-indazole (61.8 mg, 0.31 mmol, 1.10 equiv), Et₃N (0.12 mL, 0.86 mmol, 3.00 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (11.7 mg, 0.014 mmol, 0.05 equiv). The resulting solution was stirred for 5 h at 120° C. The reaction mixture was cooled to 25° C. with a water bath. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 30 mg (36%) of (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H]⁺=292 ¹H NMR (300 MHz, DMSO-d₆, ppm): 13.24 (s, 1H), 9.50 (s, 1H), 8.10 (s, 1H), 7.84-7.68 (m, 3H), 7.45-7.41 (m, 1H), 7.11 (s, 3H), 6.97 (d, J=15.9 Hz, 1H), 2.19 (s, 6H).

Examples 25 and 26: (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide, Isomer 1; (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide, Isomer 2

Step 1: Into a 100-mL round-bottom flask, was placed benzaldehyde (5.5 g, 51.83 mmol, 1.00 equiv), EtOH (30.0 mL), NH₄OAc (8.0 g, 103.65 mmol, 2.00 equiv), malonic acid (5.4 g, 51.83 mmol, 1.00 equiv). The resulting solution was stirred for 12 h at 80° C. The solids were collected by filtration. This resulted in 5 g (58%) of 3-amino-3-phenylpropanoic acid as a white solid.

Step 2: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-amino-3-phenylpropanoic acid (4.9 g, 29.66 mmol, 1.00 equiv), DCM (40.0 mL). This was followed by the addition of trifluoroacetic anhydride (6.9 g, 32.63 mmol, 1.10 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at ° C. The solids were collected by filtration. This resulted in 4 g (52%) of 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoic acid as a white solid.

Step 3: Into a 100-mL round-bottom flask, was placed 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoic acid (5.0 g, 19.14 mmol, 1.00 equiv), thionyl chloride (30 mL). The resulting solution was stirred for 3 hr at 70° C. The resulting mixture was concentrated. This resulted in 4.5 g (84%) of 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoyl chloride as a white solid.

Step 4: Into a 100-mL 3-necked round-bottom flask, was placed AlCl₃ (4.29 g, 32.18 mmol, 2.00 equiv), DCM (30.00 mL). This was followed by the addition of a solution of 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoyl chloride (4.5 g, 16.09 mmol, 1.00 equiv) in DCM (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 12 hr at 40° C. The reaction mixture was cooled to 25° C. The solids were filtered out. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/2). This resulted in 3.4 g (87%) of 2,2,2-trifluoro-N-(3-oxo-1,2-dihydroinden-1-yl)acetamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=244

Step 5: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,2,2-trifluoro-N-(3-oxo-1,2-dihydroinden-1-yl)acetamide (3.0 g, 12.34 mmol, 1.00 equiv), MeOH (30.00 mL). This was followed by the addition of NaBH₄ (1.40 g, 37.01 mmol, 3.00 equiv), in portions at 0° C. The resulting solution was stirred for 3 hr at RT. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 2×40 mL of DCM. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 2 g (66%) of 2,2,2-trifluoro-N-(3-hydroxy-2,3-dihydro-1H-inden-1-yl)acetamide as a white solid.

Step 6: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,2,2-trifluoro-N-(3-hydroxy-2,3-dihydro-1H-inden-1-yl)acetamide (2.0 g, 8.16 mmol, 1.00 equiv), DCM (30.00 mL). This was followed by the addition of diethylsulfur trifluoride (1.71 g, 10.60 mmol, 1.30 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 2 hr at 0° C. The reaction was then quenched by the addition of 50 mL of aq·NaHCO₃. The resulting solution was extracted with 2×50 mL of dichloromethane dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/5). This resulted in 810 mg (40%) of 2,2,2-trifluoro-N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)acetamide as a light yellow solid.

Step 7: Into a 40-mL vial, was placed 2,2,2-trifluoro-N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)acetamide (800.0 mg, 3.24 mmol, 1.00 equiv), MeOH/H₂O (10.0 mL/5.0 mL), NaOH (258.9 mg, 6.472 mmol, 2.00 equiv). The resulting solution was stirred for 5 h at RT. The resulting solution was extracted with 2×20 mL of EtOAc and the organic layer was dried over anhydrous sodium sulfate and concentrated. This resulted in 450 mg (92%) of 3-fluoro-2,3-dihydro-1H-inden-1-amine as a light yellow solid.

Step 8: Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-fluoro-2,3-dihydro-1H-inden-1-amine (410.0 mg, 2.71 mmol, 1.00 equiv), DCM (15.00 mL), Et₃N (0.76 mL, 5.42 mmol, 2.00 equiv). This was followed by the addition of acryloyl chloride (294.55 mg, 3.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC. This resulted in 230 mg (41%) of N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a light yellow solid.

Step 9: Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (80.0 mg, 0.39 mmol, 1.00 equiv), DMF (8.0 mL), 6-bromo-1H-indazole (84.5 mg, 0.43 mmol, 1.10 equiv), Et₃N (0.14 mL, 0.98 mmol, 2.50 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (25.40 mg, 0.03 mmol, 0.08 equiv). The resulting solution was stirred for 12 h at 120° C. The reaction mixture was cooled to 25° C. The resulting solution was diluted with 8 mL of water. The resulting solution was extracted with 2×10 mL of EtOAc. The resulting mixture was washed with 2×15 ml of brine. The resulting mixture was concentrated. The crude product was purified by SFC. This resulted in 11 mg (9%) of trans-(2E)-N-[(1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-6-yl)prop-2-enamide (Isomer 1) as a off-white solid and 13 mg (10%) of cis-(2E)-N-[(1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-6-yl)prop-2-enamide (Isomer 2) as an off-white solid.

Stereochemistries Assigned Arbitrarily:

Isomer 1: LC-MS (ES, m/z): [M+H]⁺=322

¹H NMR (300 MHz, DMSO-d₆, ppm): 13.15 (s, 1H), 8.57 (d, J=8.1 Hz, 1H), 8.09 (s, 1H), 7.77-7.56 (m, 4H), 7.50-7.34 (m, 4H), 6.73 (d, J=15.9 Hz, 1H), 6.26-6.06 (m, 1H), 5.69-5.66 (m, 1H), 2.76-2.61 (m, 1H), 2.31-2.17 (m, 1H).

Isomer 2: LC-MS (ES, m/z): [M+H]⁺=322

¹H NMR (300 MHz, DMSO-d₆, ppm): 13.16 (brs, 1H), 8.67 (d, J=8.1 Hz, 1H), 8.09 (s, 1H), 7.81-7.65 (m, 4H), 7.54-7.30 (m, 4H), 6.77 (d, J=15.6 Hz, 1H), 6.15-5.92 (m, 1H), 5.42-5.35 (m, 1H), 3.10-2.97 (m, 1H), 2.10-2.01 (m, 1H).

Example 27: (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 eq), THF (3.00 mL), 2-(phenoxymethyl)aniline (125.2 mg, 0.62 mmol, 1.20 eq), LiHMDS (2.62 mL, 2.62 mmol, 5.00 eq). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried with sodium sulfate, and concentrated. This resulted in 78 mg (crude) of N-[2-(hydroxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS-PH-NRG0347-1 (ES, m/z): [M+H]⁺=378

Step 2: Into a 8-mL sealed tube, was placed (N-[2-(hydroxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (75 mg, crude), THF (2 mL), TFA (2 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 38 mg of (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=294 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.26 (brs, 1H), 9.57 (s, 1H), 8.11 (s, 1H), 7.83-7.70 (m, 4H), 7.53-7.44 (m, 2H), 7.30-7.08 (m, 2H), 7.00 (d, J=15.9 Hz, 1H), 5.33 (brs, 1H), 4.57 (s, 2H).

Example 28: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide

Into a 8-mL vial, was placed 6-bromo-1H-indazole (100.0 mg, 0.51 mmol, 1.00 equiv), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (Prepared as for Intermediate 1 using 3-fluoro-2,6-dimethylaniline and acryloyl chloride, 98.1 mg, 0.51 mmol, 1.00 equiv), Pd(dppf)Cl₂ (37.1 mg, 0.051 mmol, 0.10 equiv) and Et₃N (0.21 mL, 1.52 mmol, 3.00 equiv) in DMF (4.0 mL). The resulting solution was stirred for 2 h at 120° C. in an oil bath. The reaction mixture was cooled. The residue was applied onto a silica gel column with THF/PE (1/1). This resulted in 20 mg (13%) of (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=310 ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 13.26 (s, 1H), 9.66 (s, 1H), 8.11 (s, 1H), 7.84-7.71 (m, 3H), 7.44 (d, J=9.3 Hz, 1H), 7.16-6.95 (m, 3H), 2.17 (s, 3H), 2.09 (s, 3H).

Example 29: (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide

Step 1: Into a 40-mL sealed tube, was placed 2-nitrobenzyl alcohol (500.00 mg, 3.26 mmol, 1.00 eq), MeCN (20.00 mL), K₂CO₃ (676.80 mg, 4.89 mmol, 1.50 eq). This was followed by the addition of methyl iodide (1.40 g, 9.79 mmol, 3.00 eq) at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2×30 mL of EtOAc. The organic phase was washed with 2×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 510 mg (93%) of 1-(methoxymethyl)-2-nitrobenzene as light yellow oil.

Step 2: Into a 40-mL sealed tube, was placed 1-(methoxymethyl)-2-nitrobenzene (510.0 mg, 3.05 mmol, 1.00 eq), EtOH (10.0 mL), H₂O (2.0 mL), NH₄Cl (1.3 mg, 24.50 mmol, 8.03 eq) and Zn (997.8 mg, 15.25 mmol, 5.00 eq). The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 50 mL of DCM. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 380 mg (90%) of 2-(methoxymethyl)aniline as a light yellow solid. LC-MS (ES, m/z): [M+H]⁺=138

Step 3: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (50.0 mg, 0.17 mmol, 1.00 eq), 2-(methoxymethyl)aniline (23.3 mg, 0.17 mmol, 1.00 eq) and THF (3.00 mL). This was followed by the addition of LiHMDS (0.70 mL, 0.70 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 0.5 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×10 mL of EtOAc. The organic phase was dried over sodium sulfate, and concentrated. This resulted in 51 mg (crude) of (2E)-N-[2-(methoxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=392

Step 4: Into a 8-mL sealed tube, was placed (2E)-N-[2-(methoxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (51.0 mg, 0.13 mmol, 1.00 eq), MeOH (2.0 mL) and 4 M HCl/MeOH (2.0 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 38 mg of (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=308 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 9.49 (s, 1H), 8.11 (s, 1H), 7.84-7.69 (m, 4H), 7.47-7.18 (m, 4H), 7.04 (d, J=15.9 Hz, 1H), 4.49 (s, 2H), 3.33 (s, 3H).

Example 30: (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide Hydrochloride

Step 1: Into a 100-mL 3-necked round-bottom flask, was placed tert-butyl 3-hydroxyazetidine-1-carboxylate (4.0 g, 23.09 mmol, 1.00 eq), DMF (50.0 mL), K₂CO₃ (4.8 g, 34.64 mmol, 1.50 eq), 1-(bromomethyl)-2-nitrobenzene (4.99 g, 23.09 mmol, 1.00 eq). The resulting solution was stirred for 3 h at 50° C. The resulting solution was diluted with 150 mL of EtOAc. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (20:80). This resulted in 3.5 g (49%) of tert-butyl 3-[(2-nitrophenyl)methoxy]azetidine-1-carboxylate as a colorless solid.

Step 2: Into a 50-mL round-bottom flask, was placed tert-butyl 3-[(2-nitrophenyl)methoxy]azetidine-1-carboxylate (3.0 g, 9.73 mmol, 1.00 eq), DCM (10.0 mL) and TFA (10.0 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated. The crude product was purified by re-crystallization from Et₂O. This resulted in 2.7 g (91%) of 3-((2-nitrobenzyl)oxy)azetidine trifluoroacetate as a white solid LC-MS (ES, m/z): [M+H]⁺=209

Step 3: Into a 40-mL sealed tube, was placed 3-((2-nitrobenzyl)oxy)azetidine trifluoroacetate (1.00 g, 3.28 mmol, 1.00 eq), MeCN (20.00 mL), K₂CO₃ (0.91 g, 6.57 mmol, 2.00 eq), KI (0.55 g, 3.31 mmol, 1.01 eq), 1-bromo-2-fluoroethane (0.63 g, 4.93 mmol, 1.50 eq). The resulting solution was stirred for 3 h at 50° C. The resulting solution was diluted with 50 mL of EA. The solids were filtered out. The filtrate was concentrated. The residue was applied onto a silica gel column with THF:PE=32:68. This resulted in 0.75 g (89%) of 1-(2-fluoroethyl)-3-[(2-nitrophenyl)methoxy]azetidine as a light yellow solid.

Step 4: Into a 40-mL sealed tube, was placed 1-(2-fluoroethyl)-3-[(2-nitrophenyl)methoxy]azetidine (500.0 mg, 1.96 mmol, 1.00 eq), MeOH (10.0 mL), H₂O (2.0 mL), NH₄Cl (841.5 mg, 15.72 mmol, 8.00 eq), Zn (643.1 mg, 9.80 mmol, 5.00 eq). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 50 mL of DCM. The solids were filtered out. The filtrate was concentrated. This resulted in 300 mg (68%) of 2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)aniline as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=225

Step 5: Into a 8-mL sealed tube, was placed methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (100.0 mg, 0.35 mmol, 1.00 eq), 2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)aniline (78.3 mg, 0.35 mmol, 1.00 eq), THF (3.00 mL). This was followed by the addition of LiHMDS (1.7 mL, 1.75 mmol, 5.00 eq) at 0° C. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×10 mL of ethyl acetate. The organic phase was dried over sodium sulfate, and concentrated. This resulted in 105 mg (crude) of (2E)-N-[2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=479

Step 6: Into a 8-mL sealed tube, was placed (2E)-N-[2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.0 mg, crude), DCM (5.0 mL), TFA (119.13 mg, 1.05 mmol, 5.00 eq). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 73 mg of (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=395

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 11.40-10.90 (m, 1H), 9.77-9.73 (m, 1H), 8.11 (s, 1H), 7.84-7.62 (m, 4H), 7.47-7.11 (m, 5H), 4.79-4.58 (m, 4H), 4.45-3.96 (m, 5H), 3.65-3.52 (m, 2H).

Example 31: (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 40-mL sealed tube, was placed 1-(bromomethyl)-2-nitrobenzene (500.0 mg, 2.31 mmol, 1.00 equiv), CH₃CN (10.0 mL), Et₃N (0.64 mL, 4.63 mmol, 2.00 eq), 3-fluoroazetidine hydrochloride (309.8 mg, 2.77 mmol, 1.20 eq). The resulting solution was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×20 mL of EtOAc. The organic phase was washed with 20 ml of brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/PE (20:80). This resulted in 380 mg (78%) of 3-fluoro-1-[(2-nitrophenyl)methyl]azetidine as an off-white solid.

Step 2: Into a 40-mL vial, was placed 3-fluoro-1-[(2-nitrophenyl)methyl]azetidine (380.0 mg, 1.81 mmol, 1.00 eq), MeOH (8.0 mL), H₂O (1.0 mL), NH₄Cl (773.6 mg, 14.46 mmol, 8.00 eq) and Zn (591.2 mg, 9.04 mmol, 5.00 eq). The resulting solution was stirred for 2 h at room temperature and diluted with 30 mL of DCM. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 310 mg (95%) of 2-[(3-fluoroazetidin-1-yl)methyl]aniline as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=181

Step 3: Into a 8-mL sealed tube, was placed methyl (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 70.0 mg, 0.244 mmol, 1.00 eq), THF (2.0 mL), 2-[(3-fluoroazetidin-1-yl)methyl]aniline (52.9 mg, 0.29 mmol, 1.20 eq). This was followed by the addition of LiHMDS (1.2 mL, 1.22 mmol, 5.00 eq) at 0° C. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×10 mL of EtOAc. The organic phase was dried over sodium sulfate and concentrated. This resulted in 55 mg (crude) of (2E)-N-[2-[(3-fluoroazetidin-1-yl)methyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=435

Step 4: Into a 8-mL sealed tube, was placed (2E)-N-[2-[(3-fluoroazetidin-1-yl)methyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (55.0 mg, crude), DCM (2.0 mL) and TFA (2.0 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 18 mg of (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=351 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.26 (s, 1H), 10.22 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.84-7.71 (m, 3H), 7.52-7.49 (m, 1H), 7.32-7.27 (m, 2H), 7.12-7.07 (m, 1H), 6.95 (d, J=15.6 Hz, 1H), 5.36-5.17 (m, 1H), 3.77 (s, 2H), 3.69-3.58 (m, 2H), 3.27-3.16 (m, 2H).

Example 32: (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 50-mL round-bottom flask, was placed 2-nitrobenzaldehyde (0.90 g, 5.95 mmol, 1.00 eq), bromo(methyl)triphenyl-lambda5-phosphane (3.20 g, 8.93 mmol, 1.50 eq) and THF (30.0 mL). This was followed by the addition of t-BuOK (1.0 g, 8.93 mmol, 1.50 eq) at 0° C. The resulting solution was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 30 mL of 2 M HCl. The resulting solution was extracted with 50 mL of EtOAc. The organic phase was washed with 20 ml of brine. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5:95). This resulted in 270 mg (30%) of 1-ethenyl-2-nitrobenzene as a light yellow solid.

Step 2: Into a 8-mL sealed tube, was placed 1-ethenyl-2-nitrobenzene (270.0 mg, 1.81 mmol, 1.00 eq), MeOH (4.0 mL), Et₃N (0.5 mL, 3.62 mmol, 2.00 eq), 3-fluoroazetidine (149.5 mg, 1.99 mmol, 1.10 eq). The resulting solution was stirred for 20 h at room temperature. The resulting mixture was concentrated under low temp. The residue was applied onto a silica gel column with EtOAc/PE (20:80). This resulted in 190 mg (46%) of 3-fluoro-1-[2-(2-nitrophenyl)ethyl]azetidine as a light yellow solid.

Step 3: Into a 40-mL sealed tube, was placed 3-fluoro-1-[2-(2-nitrophenyl)ethyl]azetidine (190.0 mg, 0.85 mmol, 1.00 eq), MeOH (6.0 mL), H₂O (1.0 mL), NH₄Cl (362.6 mg, 6.77 mmol, 8.00 eq), Zn (277.1 mg, 4.24 mmol, 5.00 eq). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 20 mL of DCM. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated. This resulted in 150 mg (91%) of 2-[2-(3-fluoroazetidin-1-yl)ethyl]aniline as an off-white solid.

LC-MS (ES, m/z): [M+H]⁺=195

Step 4: Into a 8-mL sealed tube, was placed (E)-methyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (60.0 mg, 0.21 mmol, 1.00 eq), 2-[2-(3-fluoroazetidin-1-yl)ethyl]aniline (40.7 mg, 0.21 mmol, 1.00 eq) and THF (2.0 mL). This was followed by the addition of LiHMDS (0.84 mL, 0.84 mmol, 4.00 eq) at 0° C. The resulting solution was stirred for 0.5 h at room temperature. The reaction was then quenched by the addition of 5 mL of Sat NH₄Cl. The resulting solution was extracted with 2×10 mL of EtOAc. The organic phase was dried over Na₂SO₄, and concentrated. This resulted in 51 mg (crude) of N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a solid.

LC-MS (ES, m/z): [M+H]⁺=449

Step 5: Into a 8-mL sealed tube, was placed N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (51.00 mg, crude), DCM (1.00 mL), TFA (1.00 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under low temp. The crude product was purified by Flash-Prep-HPLC. This resulted in 18 mg of (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=365 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.25 (brs, 1H), 10.02 (s, 1H), 8.11 (s, 1H), 7.83-7.72 (m, 3H), 7.63-7.60 (m, 1H), 7.46-7.43 (m, 1H), 7.26-7.12 (m, 3H), 7.01 (d, J=15.9 Hz, 1H), 5.25-5.06 (m, 1H), 3.61-3.50 (m, 2H), 3.21-3.09 (m, 2H), 2.65 (s, 4H).

Example 33: (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide

Step 1: Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-fluoro-6-methylaniline (160.0 mg, 1.28 mmol, 1.00 equiv), DCM (6.0 mL), Et₃N (0.45 mL, 3.20 mmol, 2.50 equiv). This was followed by the addition of acryloyl chloride (138.86 mg, 1.54 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/6). This resulted in 120 mg (52%) of N-(2-fluoro-6-methylphenyl)prop-2-enamide as a light yellow solid.

LC-MS-PH-NRG0405-1 (ES, m/z): [

Step 2: Into a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-(2-fluoro-6-methylphenyl)prop-2-enamide (120.0 mg, 0.67 mmol, 1.00 equiv), DMF (5.0 mL), 6-bromo-1H-indazole (145.1 mg, 0.74 mmol, 1.10 equiv), Et₃N (0.28 mL, 2.01 mmol, 3.00 equiv) and Pd(dppf)Cl₂·CH₂Cl₂ (27.28 mg, 0.034 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 120° C. The reaction mixture was cooled to room temperature. The crude mixture was purified by Prep-HPLC. This resulted in 30 mg (15%) of (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide as a off-white solid. LC-MS (ES, m/z): [M+H]⁺=296 ¹H NMR (300 MHz, DMSO-d₆, ppm): 9.70 (s, 1H), 8.11 (s, 1H), 7.84-7.70 (m, 3H), 7.43 (d, J=8.1 Hz, 1H), 7.27-7.20 (m, 1H), 7.14-7.08 (m, 2H), 6.97 (d, J=15.9 Hz, 1H), 2.24 (s, 3H).

Example 34: (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide

To a microwave vial with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 100.00 mg, 0.558 mmol, 1.00 equiv), 6-bromo-1H-pyrazolo[4,3b]pyridine (110 mg, 0.558 mmol, 1.00 equiv), Pd(OAc)₂ (19 mg, 0.084 mmol, 0.15 equiv) tris(2-methylphenyl)phosphane (34 mg, 0.112 mmol, 0.20 equiv) and tetrabutylammonium chloride (155 mg, 0.558 mmol, 1.00 equiv) was added DMF (1.5 mL). The resulting solution was stirred for 12 h at 115° C. The resulting mixture was diluted with 20 mL EtOAc washed with 2×10 mL of 1 M aq. K₂CO₃ and the organic layer was concentrated and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column. The resulting crude product was purified by Flash-Prep-HPLC. This resulted in 23 mg (14%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide as a white solid. LC-MS (ES, m/z): [M+H]⁺=297 ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 13.55 (s, 1H), 9.71 (s, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.0 Hz, 1H), 8.25 (d, J=1.7 Hz, 1H) 7.82 (d, J=15.9 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.30-7.16 (m, 2H), 7.03 (t, J=9.1 Hz, 1H), 2.18 (s, 3H).

Example 35: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide

Into a 8-mL vial, was placed 6-bromo-1H-pyrazolo[4,3-c]pyridine (Example 9, Step 1, 200.0 mg, 1.01 mmol, 1.00 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (189.1 mg, 1.01 mmol, 1.00 equiv), Pd(dppf)Cl₂ (73.9 mg, 0.10 mmol, 0.10 equiv) and Et₃N (0.42 mL, 3.03 mmol, 3.00 equiv) in DMF (5.00 mL). The resulting solution was stirred for 15 h at 120° C. in an oil bath. The reaction mixture was cooled. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 15 mg (5%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide as a white solid. LC MS (ES, m/z): [M+H]⁺=305

¹H NMR (300 MHz, DMSO-d₆, ppm): δ 9.05 (s, 1H), 8.58 (d, J=8.1 Hz, 1H), 8.26 (s, 1H), 7.71 (s, 1H), 7.64 (d, J=15.0 Hz, 1H), 7.33-7.16 (m, 5H), 5.49-5.40 (m, 1H), 3.02-2.81 (m, 2H), 2.46-2.40 (m, 1H), 1.90-1.81 (m, 1H).

Example 36: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide

Into a 8-mL round-bottom flask, was placed 6-bromo-1H-pyrazolo[3,4-b]pyridine (Example 9, Step 1, 200.0 mg, 1.01 mmol, 1.00 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (189.1 mg, 1.01 mmol, 1.00 equiv), Pd(dppf)Cl₂CH₂Cl₂ (82.5 mg, 0.10 mmol, 0.10 equiv), Et₃N (0.42 mL, 3.03 mmol, 3.00 equiv), DMF (4.00 mL). The resulting solution was stirred for 15 hat 120° C. in an oil bath. The reaction mixture was cooled. The crude mixture was purified by Flash-Prep-HPLC. This resulted in 15 mg (5%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide as a solid. LC-MS (ES, m/z): [M+H]⁺=305 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.75 (d, J=8.4 Hz, 1H), 8.27 (d, J=8.1 Hz, 1H), 8.16 (s, 1H), 7.63 (d, J=15.3 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.39-6.99 (m, 6H), 5.50-5.40 (m, 1H), 3.07-2.77 (m, 2H), 2.48-2.37 (m, 1H), 1.94-1.74 (m, 1H).

Example 37: (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

Step 1: Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (2.6 g, 17.43 mmol, 1.00 equiv), DMF (50.0 mL), Et₃N (4.9 mL, 34.85 mmol, 2.00 equiv), phthalic anhydride (3.9 g, 26.14 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 200 mL of water. The pH value of the solution was adjusted to 5-6 with 2N HCl. The resulting solution was extracted with 3×100 mL of EtOAc. The resulting mixture was washed with 1×100 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc-PE (1:5-1:3). This resulted in 3.60 g (74%) of 2-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione as an off-white solid.

Step 2: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione (2.0 g, 7.16 mmol, 1.00 equiv), DMF (30.0 mL), BaO (13.2 g, 85.93 mmol, 12.00 equiv), Ba(OH)₂ (7.4 g, 42.97 mmol, 6.00 equiv) and CH₃I (6.1 g, 42.98 mmol, 6.00 equiv). The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:6-1:4). This resulted in 1.60 g (76%) of 2-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione as an off-white solid.

Step 3: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione (1.60 g, 5.46 mmol, 1.00 equiv), EtOH (50.0 mL), NH₂NH₂·H₂O (80%, 15 mL). The resulting solution was heated to reflux overnight. The reaction mixture was cooled to room temperature. The solids were filtered out. The resulting mixture was concentrated. The resulting solution was diluted with 200 mL of EtOAc. The resulting mixture was washed with 2×100 of H₂O and 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF:PE (1:3-1:1). This resulted in 250 mg (28%) of (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine as an off-white solid.

Step 4: Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine (250.0 mg, 1.53 mmol, 1.00 equiv), (2E)-3-1 methyl 3-(1H-indazol-6-yl) acrylate (Intermediate 3, 458.8 mg, 1.69 mmol, 1.10 equiv), HATU (873.6 mg, 2.30 mmol, 1.50 equiv), DMF (10 mL), DIPEA (593.88 mg, 4.60 mmol, 3.00 equiv). The resulting solution was stirred for 4 hr at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×60 mL of EtOAc. The organic layer was washed with 1×50 ml of brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF:PE (1:3-1:1). This resulted in 200 mg (31%) of (2E)-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

Step 5: Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2E)-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (200.0 mg, 0.48 mmol, 1.00 equiv), 4 M HCl in EtOAc (10.00 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC. This resulted in 27 mg (17%) of (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=334 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (brs, 1H), 8.58 (d, J=8.7 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.37-7.34 (m, 1H), 7.27-7.18 (m, 4H), 6.75 (d, J=15.6 Hz, 1H), 5.35-5.30 (m, 1H), 4.07-4.01 (m, 1H), 3.38 (s, 3H), 3.35-3.27 (m, 1H), 2.84-2.76 (m, 1H).

Example 38: (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

Step 1: Into a 8-mL sealed tube, was placed methyl 3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (150.0 mg, 0.52 mmol, 1.00 eq), 7-methyl-2,3-dihydro-1H-inden-1-amine (154.3 mg, 1.05 mmol, 2.00 eq) and THF (3.00 mL). This was followed by the addition of LiHMDS (2.1 mL, 2.09 mmol, 4.00 eq) at room temperature. The resulting solution was stirred for 0.5 h at room temperature. The reaction was then quenched by the addition of 20 mL of Sat NH₄Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried by Na₂SO₄ and concentrated. This resulted in 130 mg (crude) of N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

Step 2: Into a 20-mL round-bottom flask, was placed N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (130.0 mg, crude), MeOH (4.00 mL), 4 M HCl in dioxane (4.00 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC. This resulted in 21 mg of (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=318 ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 13.21 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.07 (s, 1H), 7.78-7.59 (m, 3H), 7.32-6.99 (m, 4H), 6.70 (d, J=15.6 Hz, 1H), 5.52-5.45 (m, 1H), 3.09-2.78 (m, 2H), 2.49-2.34 (m, 1H), 2.22 (s, 3H), 1.92-1.85 (m, 1H).

Example 39: (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

Step 1: Into a 40-mL vial, was placed 3-methyl-2,3-dihydroinden-1-one (500.0 mg, 3.42 mmol, 1.00 equiv), NH₂OH·HCl (237.7 mg, 3.42 mmol, 1.00 equiv), Et₃N (1.4 mL, 10.26 mmol, 3.00 equiv) in MeOH (12.00 mL). The resulting solution was stirred for 10 h at 70° C. in an oil bath. The reaction mixture was cooled and concentrated. The residue was applied onto a silica gel column with EtOAc/PE (1/1). This resulted in 400 mg (72%) of N-[(1Z)-3-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine as a white solid.

Step 2: Into a 50-mL round-bottom flask, was placed N-[(1Z)-3-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine (400.0 mg, 2.481 mmol, 1.00 equiv) in 4 M HCl/MeOH (2.0 mL) and MeOH (10.0 mL). was added Pd/C (264 mg). The resulting solution was stirred for 10 h at 20° C. under H₂ (30 Psi). The solution was collected by filtration. The resulting mixture was concentrated. This resulted in 350 mg (77%) of 3-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride as a white solid.

Step 3: Into a 8-mL round-bottom flask, was placed 3-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (100.0 mg, 0.54 mmol, 1.00 equiv), methyl 3-(1H-indazol-6-yl) acrylate (Intermediate 3, 148.3 mg, 0.54 mmol, 1.00 equiv), HATU (310.5 mg, 0.82 mmol, 1.50 equiv) and Et₃N (0.23 mL, 1.63 mmol, 3.00 equiv) in DMF (2.0 mL). The resulting solution was stirred for 2 h at 20° C. The residue was applied onto a silica gel column with THF/PE (1/1). This resulted in 110 mg (50%) of (2E)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a white solid.

Step 4: Into a 8-mL vial, was placed (2E)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.00 mg, 0.25 mmoL, 1.00 equiv), 4 M HCl/MeOH (2.00 mL) and MeOH (2.00 mL). The resulting solution was stirred for 2 h at 20° C. The mixture was purified by Flash-Prep-HPLC with HCl. This resulted in 20 mg (25%) of (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as a solid. LC-MS (ES, m/z): [M+H]⁺=318 ¹H-NMR (300 MHz, DMSO-d₆, ppm) δ 8.52-8.48 (m, 1H), 8.08 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.72-7.61 (m, 2H), 7.35 (d, J=8.4, 1H), 7.34-7.20 (m, 4H), 6.78 (d, J=15.6 Hz, 1H), 5.41-5.35 (m, 1H), 3.12-3.00 (m, 1H), 2.70-2.60 (m, 1H), 1.50-1.33 (m, 4H).

Example 40: (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide

Step 1: Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2E)-N-[2-(hydroxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (Example 27, 200.0 mg, 0.53 mmol, 1.00 equiv), THF (5.00 mL). This was followed by the addition of NaH (19.1 mg, 0.80 mmol, 1.50 equiv) at 0° C. The resulting solution was stirred for 10 min at 0° C. To this was added propargyl bromide (63.0 mg, 0.53 mmol, 1.00 equiv) at 0° C. The resulting solution was warmed to room temperature stirred for 2 h. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2×8 mL of EtOAc and dried over anhydrous sodium sulfate. The resulting mixture was concentrated. The residue was purified by Prep-HPLC. This resulted in 55 mg (25%) of (2E)-3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-[(prop-2-yn-1-yloxy)methyl]phenyl]prop-2-enamide as a light yellow solid.

Step 2: Into a 20-mL vial, was placed (2E)-3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-[(prop-2-yn-1-yloxy)methyl]phenyl]prop-2-enamide (55.00 mg, 0.13 mmol, 1.00 equiv), 4 M HCl/dioxane (5.00 mL). The resulting solution was stirred for 3 h at room temperature. The pH of the solution was adjusted to 8 with 2 M Na₂CO₃. The resulting solution was extracted with 2×10 mL of EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC. This resulted in 5.1 mg (12%) of (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide as an off-white solid. LC-MS (ES, m/z): [M+H]⁺=332 ¹H NMR (300 MHz, DMSO-d₆, ppm): 13.28 (brs, 1H), 9.54 (brs, 1H), 8.11 (s, 1H), 7.84-7.66 (m, 3H), 7.46-7.30 (m, 3H), 7.21 (s, 1H), 7.12-6.95 (m, 2H), 4.60 (s, 2H), 4.23 (d, J=2.1 Hz, 2H), 3.55-3.50 (m, 1H).

Biological Examples Biological Example 1—mPTP Activity Assay in Isolated Rat Liver Mitochondria, Human Platelet Mitochondria and Isolated Rat Brain Mitochondria

Rat Liver Mitochondria Assay

Pharmacological inhibition or modulation of the mPTP can be measured in well characterised ‘Ca²⁺ retention’ assays performed in isolated mitochondria. In vitro, isolated mitochondria rapidly sequester exogenous Ca²⁺ until the intramitochondrial Ca²⁺ concentration reaches the threshold for mPTP activation. Once the pore is activated, mitochondrial integrity is compromised and the stored Ca²⁺ is released. The distribution of Ca²⁺ between extra- and intra-mitochondrial compartments can be measured in real time with the use of membrane-impermeant Ca²⁺ sensitive fluorescent dyes. Depending on the configuration of the assay, inhibition or modulation of the mPTP either delays the opening of the pore or increases the concentration of Ca²⁺ required to induce mPTP opening.

mPTP activity was measured in mitochondria freshly isolated from female Sprague Dawley (250 to 300 gram) rat livers using the following method. Cervical dislocation was performed on the rat. The liver was then perfused in-situ with ˜40 ml cold Dulbecco's Phosphate Buffered Saline (DPBS) prior to dissection and transferred into 30 ml Isolation Buffer (250 mM Sucrose, 10 mM KCl, 1 mM EGTA, 1 mM EDTA, 25 mM HEPES, adjusted to pH 7.5 with 1 M NaOH). Each lobe of the liver was then removed from the buffer, minced using tweezers and a scalpel into ˜5 mm pieces then transferred into a 50 ml Potterton dounce homogenization tube on ice containing 30 ml ice-cold centrifugation buffer (300 mM Trehalose, 25 mM HEPES, 1 mM EGTA, 1 mM EDTA, 10 mM KCl, adjusted to pH 7.5 with 1 M NaOH and supplemented with 0.1% bovine serum albumin (BSA) and complete protease inhibitor cocktail (one tablet of inhibitor per 50 mls of buffer). Homogenisation was carried out using a teflon pestle at 1800 rpm. The slurry was centrifuged at 800 g for 10 min at 4° C., then the supernatant centrifuged at 10,000 g for 10 min. The pellet was washed once with FLIPR assay buffer (75 mM Mannitol, 25 mM Sucrose, 5 mM Potassium Phosphate Monobasic, 20 mM Tris base, 100 mM KCl, 0.1% BSA adjusted to pH 7.4 with 5 M HCl) centrifuged again, then resuspended in FLIPR assay buffer to a concentration of 8.8 mg/ml protein.

Test compounds (10 mM stock in DMSO) were serially diluted in DMSO in half log steps to generate 10 test concentrations (final concentrations in assay 30 μM to 1 nM). An intermediate dilution of 5 μl DMSO samples into 247 μl FLIPR assay buffer was carried out prior to transfer of 5 μl into duplicate wells of a 384 well polypropylene assay plate. Control wells were 0.5% (v/v) DMSO and 5 μM cyclosporin A.

A stock mitochondria/Fluo5N assay solution was prepared in 5.6 ml FLIPR assay buffer (at RT) supplemented with succinate disodium salt (10 mM), rotenone (1 μM), Fluo5N pentapotassium salt (2 μM) and 1 ml mitochondria suspension, then transferred (15 μl) into the assay plate containing test compounds and incubated for 10 min at RT. Assay plates were then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 sec for a total of 10 min. After 12 sec, a 2.5 μl bolus of CaCl₂ (75 μM) was added from a source plate containing 675 μM CaCl₂ in FLIPR assay buffer. IC50 values for test compounds were calculated using the fluorescence value collected at the 10 min timepoint with % inhibition calculated using the DMSO control and cyclosporin A values as 100 and 0% respectively.

Human Platelet Mitochondria Assay

The mPTP cell based assay was performed using a mitochondria membrane potential flow cytometry assay in stimulated human platelets. Simulation of platelets results in the rapid influx of Ca²⁺ across the platelet membrane. The Ca²⁺ is then sequestered by mitochondria until the threshold for mPTP opening is reached, at which point the pore opens and the mitochondrial membrane potential is dissipated. Changes in mitochondria membrane potential due to mPTP opening can be quantified in live platelets using standard mitochondrial membrane potential dyes e.g. 3,3′-dihexyloxacarbocyanine Iodide; DiOC6 (3), enabling pharmacological characterisation of mPTP inhibitors.

Fresh human blood (20 ml) was collected from consented donors into 3.2% sodium citrate. Platelets were isolated by centrifugation at 200 g for 20 min at room temperature, then the platelet rich plasma layer transferred to a fresh tube. Prostaglandin 12 is added to the platelets at a final concentration of 20 ng/ml. After centrifugation at 640 g for 10 min, the platelet rich pellet was resuspended in 4 ml HEPES assay buffer (137 mM NaCl, 2.7 mM KCl, 11.9 mM NaHCO₃, 0.42 mM NaH₂PO₄, 1 mM MgCl₂, 5.5 mM glucose, 0.1% bovine serum albumin, 10 mM HEPES adjusted to pH 7.4) and stored on ice.

Test compounds were prepared from 10 mM stocks in DMSO and serially diluted in assay buffer containing 0.4% DMSO and 25 μl transferred into a 96 well plate. Platelets were loaded with the mitochondrial membrane potential dye DiOC6 (3) (3,3′-dihexyloxacarbocyanine Iodide; Invitrogen) at 200 nM for 30 min, then 50 μl plated into each well of the 96 well plate containing diluted test compound and incubated for 15 min. Control wells included DMSO (0.1% final concentration) only or 5 μM cyclosporin A. Platelets were then stimulation with the addition of assay buffer (25 μl) containing CaCl₂, alpha thrombin and Convulxin to achieve a final concentrations of 2 mM, 0.017 U/ml and 0.167 μg/ml respectively and incubated for 14 min. The reaction was stopped by the addition of 25 μl 15 mM EDTA in assay buffer. The mitochondrial membrane potential across the population of platelets in each well was then quantified by flow cytometry using a Guava easyCyte 5 Benchtop Flow Cytometer with 3000 events per well. The percentage of platelets with a depolarised mitochondrial membrane potential was calculated for each well. A pIC50 for each compound was then calculated using a standard four parameter curve fit model (GraphPad Prism).

Rat Brain Mitochondria Assay

MPTP activity was measured in brain mitochondria freshly isolated from female Sprague Dawley (250 to 300 gram) rats. Anaesthetised rats were perfused in-situ with ˜40 ml cold Dulbecco's Phosphate Buffered Saline (DPBS), then brains dissected and transferred into 30 ml Isolation Buffer (225 mM mannitol, 75 mM sucrose, 1 mM EGTA, adjusted to pH 7.4 with 1 M NaOH). The brain was minced using tweezers and a scalpel into ˜5 mm pieces then transferred into a 50 ml Potterton Dounce homogenization tube on ice containing 10 ml ice-cold isolation buffer (as above with addition of Complete Protease inhibitor; 1 tablet per 50 ml buffer). Homogenisation was carried out using a teflon pestle at 1800 rpm. The slurry was centrifuged at 2000 g for 10 min at 4° C., then the supernatant centrifuged at 12,000 g for 9 min. The pellet was resuspended with a dounce homogeniser in isolation buffer as above but with the addition of 0.02% digitonin, centrifuged at 12,000 g for 11 min and finally resuspended in 5 ml modified isolation buffer (as above but with EGTA reduced to 0.1 mM).

Test compounds were prepared in 384 well polypropylene assay plates as described above for the liver mitochondria assay. A stock mitochondria/Fluo5N assay solution was prepared in 5.6 ml assay buffer (120 mM mannitol, 40 mM MOPS, 5 mM KH₂PO₄, 60 mM KCl, 10 mM pyruvate, 2 mM malate, 2 mM MgCl₂, 20 μM ADP, 1.26 μM oligomycin A, adjusted to pH 7.4) supplemented with Fluo5N pentapotassium salt (2 μM) and 1 ml mitochondria suspension, then transferred (15 μl) into the assay plate containing test compounds and incubated for 10 min at RT. Assay plates were then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 sec for a total of 10 min. After 12 sec, a 2.5 μl bolus of Ca2+(75 μM) was added from a source plate containing 675 μM CaCl₂ in FLIPR assay buffer. IC50 values for test compounds were calculated using the fluorescence value collected at the 10 min timepoint with % inhibition calculated using the DMSO control and cyclosporin A values at 100% and 0% respectively.

General cytotoxicity was assessed using standard cell viability methods (Cell Titre Glo; Promega) in HEK293 and SHSY5Y cells, following incubation of test compound for between 24 and 96 hours.

Results: mPTP pIC₅₀ values for certain Example compounds in a range of mPTP assays are provided in Table 2 below. Table 2 also provides the pIC₅₀ value for Comparative Example 1. The results indicate that the tested compounds of the invention display inhibition of mPTP, with many Example compounds displaying PIC₅₀ values of 6.0 or greater. Examples 28 and 14c showed the highest activity in the rat liver mitochondria assay and Example 14c showed the highest activity in the rat brain mitochondria assay. Table 2 also provides mPTP human platelet pIC₅₀ values for certain Example compounds and for Comparative Example 1. Table 2 also provides mPTP rat brain mitochondria pIC₅₀ values for certain Example compounds and Comparative Example 1. These results indicate that the tested Example compounds are active against isolated rat liver mitochondria, isolated rat brain mitochondria and human platelet mitochondria.

Biological Example 2—PBS and FaSSIF Solubility

Test compounds were prepared as 10 mM stocks in DMSO and 15 μl samples transferred in duplicate into 1.5 mL glass flat bottom vials (BioTech Solutions). Fasted state simulated intestinal fluid (FaSSIF) or PBS (pH 7.4) was added to each vial to final volume of 500 μl. One PTFE encapsulated stir stick (V&P Scientific) was placed in each vial before sealing with PTFE/SIL plugs (BioTech Solutions). Vials were shaken at 1100 rpm for 2 hr at 25° C. Samples were then filtered through MultiScreen Solvinert filter plates (Millipore) via vacuum filtration. Aliquots of filtrate (5 μl) plus 5 μl DMSO were diluted in 490 μl 50% acetonitrile in water containing internal standard. The filtrate was analysed and quantified against a standard of known concentration using LC-MS/MS. Solubility values of the test compound and control compound were calculated as follows:

[Sample]=(Area ratio_(sample)*INJ VOL STD*DF_(sample)*[STD])/(Area ratio STD*INJ VOL_(sample)).

Results: The solubility values for certain compounds of the invention are provided in Table 2 below. Table 2 also provides results for Comparative Example 1. The results indicate that certain Example compounds display higher solubility in PBS and/or FaSSIF than Comparative Example 1. Certain compounds of the invention display higher solubility values in either PBS or FaSSIF, whilst certain compounds of the invention display higher solubility values in both PBS and FaSSIF. Therefore, certain compounds of the invention may be expected to display improved bioavailability and/or improved systemic exposure than Comparative Example 1, particularly when said compounds are dosed orally.

TABLE 2 Results of Biological Examples 1 and 2 mPTP mPTP Human mPTP Rat Solubility Solubility Example Rat liver platelets brain PBS uM FaSSIF Number pIC₅₀* pIC₅₀ pIC₅₀ (pH 7.4) (uM) Comparative 8.0 6.9 7.6 0.9 4 Example 1  1 7.1 0.11 2  2 7.6 10  3 7.2 7.3 7.3 2.2 7  4 6.3 5.2  4a 6.5  4b 6.3  5 6.3 2.5  6 6.0 4.9 9.1  7 7.2 4.1  8 6.9 6.3  9 7.2 0.4 11 10 7.6 11 7.3 1.4 12 6.0 13 7.0 4 14 7.3 14c 7.9 6.8 8.4 0.6 8 14d 6.2 15 6.9 5.9 15d 7.6 7.6 2 7 16 6.0 17 6.9 18 6.7 19 7.6 0.08 20 7.5 1.3 21 6.5 22 6.4 23 5.9 24 7.6 7.6 1.2 3 25 6.6 26 6.2 27 6.8 28 8.1 29 7.1 6.8 29 73 30 5.8 31 6.3 59 32 5.8 296 33 7.0 34 6.0 13 35 5.7 36 6.3 45 37 7.5 80 38 5.0 39 5.8 40 7.1 *average value from multiple experiments (n ≥ 2).

Biological Example 3—Liver Microsome and Hepatocyte Intrinsic Clearance Assays

Hepatocyte Clearance Assay

In vitro clearance studies were performed in primary rat and human hepatocytes (BioIVT). Vials of cryopreserved rat or human hepatocytes were thawed in a 37° C. water bath for 2 min. Cells were transferred into thawing medium (Williams' Medium E containing 30% Percoll, 1× GlutaMAX-1, 15 mM HEPES, 5% fetal bovine serum (FBS), 4 μg/ml insulin, 1 μM dexamethasone), centrifuged at 100 g for 10 min then resuspended in culture medium (Leibovitz's L-15 Medium) at a concentration of 0.5×10⁶ viable cells/mL (number of viable cells assessed using AO/PI staining). Hepatocytes (198 μL) were transferred into wells of a 96-well non-coated plate and placed in a 37° C. incubator for 10 min. Test compound solutions were prepared from 10 mM stocks in DMSO, diluted to 100 μM in 50% (v/v in water) acetonitrile. Test compound samples (2 μl) were added to each well of hepatocytes and incubated at 37° C. Samples (25 μl) were collected at t=0, 15, 30, 60, 60 and 120 min, mixed with 6 volumes (150 μl) of acetonitrile containing internal standard (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide), vortexed for 5 min and centrifuged for 45 min at 3220 g. An aliquot of supernatant (100 μL) was diluted with 100 μL ultra-pure water, and the mixture was used for LC/MS/MS analysis. All incubations were performed in duplicate. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1/2) was determined from the slope value: in vitro t1/2=0.693/k. Conversion of the in vitro t1/2 (in min) into the in vitro intrinsic clearance (in vitro CL_(int), in μL/min/1×10⁶ cells) was done using the following equation (mean of duplicate determinations):

-   -   in vitro CL_(int)=kV/N     -   V=incubation volume (0.2 mL)     -   N=number of hepatocytes per well (0.1×10⁶ cells).

Microsomal Clearance Assay

The microsomal stability of test compounds was evaluated using rat liver microsomes (BioIVT) with and without the cofactors nicotinamide adenine dinucleotide phosphate (NADPH) and uridine-diphosphate-glucuronic acid (UDPGA). Reactions were performed in a final volume of 250 μl pre-warmed (37° C.) 100 mM phosphate buffer containing 5 mM MgCl₂, 0.025 mg/ml alamethicin, and 0.5 mg/ml rat liver microsomes. NADPH and UDPGA were included at 1 mM and 2 mM respectively, where appropriate. Reactions were started with the addition of 1 μM (final concentration) test compound. Verapamil was used as the positive control. Solutions were incubated in a water bath at 37° C. and aliquots collected at 0.5, 5, 15, 30 and 60 min. Reactions were stopped by the addition of 5 volumes of cold acetonitrile with internal standards (200 nM caffeine and 100 nM tolbutamide). Samples were centrifuged at 3220 g for 40 min. An aliquot of supernatant was diluted 1:1 In ultra-pure H20, then used for LC-MS/MS analysis. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1/2) was determined from the slope value: in vitro t1/2=0.693/k. Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro CL_(int), in μL/min/mg protein) was done using the following equation (mean of duplicate determinations):

in vitro Clint=(0.693/t1/2)*(Vol of incubation (μl)/amount of protein (mg)).

Results: Intrinsic clearance values for certain Example compounds are presented in Table 3. Table 3 also presents intrinsic clearance values for Comparative Example 1. These results indicate that certain Example compounds may be expected to display improved oral bioavailability and/or improved systemic exposure when compared to Comparative Example 1 i.e. they exhibited lower intrinsic clearance (CL_(int)) values in at least human or rat species. Certain Example compounds exhibited lower intrinsic clearance (CL_(int)) values than Comparative Example 1 in both human and rat species.

TABLE 3 Results of Biological Example 3 Rat heps Rat liver Human heps intrinsic microsomes intrinsic clearance intrinsic clearance (CL_(int)) clearance (CL_(int)) Example (uL/min/10⁶ (CL_(int)) (uL/min/10⁶ Number cells)* (uL/min/mg)* cells)* Comparative 89 43 13 Example 1  1 118  2 33 59 13.99  3 28 52  4 68 39  5 55  6 59  7 38  8 41  9 61 10 60 11 45 58 26.7 13 95 14c 48 40.44 15 20 15d <3.0 <3.0 19 179 20 10 28 21 29 10 10 <3 31 101 36 32 64 31 34 51 36 12 37 25 13 *average value from two experiments.

Conclusion: The results of Biological Examples 1 to 3 demonstrate that the tested compounds of the invention are inhibitors of mPTP in a range of mPTP assays. Certain tested compounds of the invention also showed improved solubility and/or lower intrinsic clearance compared to Comparative Example 1. Therefore, certain compounds of the invention are expected to have improved pharmacokinetic profiles compared to Comparative Example 1, such as improved oral bioavailability and/or improved systemic exposure and are expected to be useful pharmaceuticals, particularly for the treatment or prophylaxis of diseases and disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

REFERENCES

-   Yu et al., TDP-43 Triggers Mitochondrial DNA Release via mPTP to     Activate cGAS/STING in ALS, Cell, Volume 183, Issue 3, 2020, pages     636-649.e18. Jang et al., Proximal tubule cyclophilin D mediates     kidney fibrogenesis in obstructive nephropathy, 2021, American     Journal of Physiology: Renal physiology, doi:     10.1152/ajprenal.00171.2021. Epub ahead of print. PMID: 34396791. -   Plyte et al., Cinnamic Anilides as New Mitochondrial Permeability     Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury     Protective Effect in Vivo, J. Med Chem. 2014, 57, 5333-47. -   Chen et al., Probing Mitochondrial Permeability Transition Pore     Activity in Nucleated Cells and Platelets by High-Throughput     Screening Assays Suggests Involvement of Protein Phosphatase 2B in     Mitochondrial Dynamics, Assay and Drug Development Technologies,     2018, 16, 445-45. 

1.-56. (canceled)
 57. A compound of formula (I):

wherein: R_(1a) is H or methyl; R_(1b) is H or fluoro; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is:

wherein: R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH), C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkylene(4-7 membered heterocycloalkyl), C₁₋₄ alkoxy, OC₁₋₄ alkylene(aryl), C₁₋₄ alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl), C₁₋₄ alkyleneO(aryl), C₃₋₆ alkynyl and C₁₋₄ alkyleneO(C₃₋₆ alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl are optionally substituted by 1, 2 or 3 substituents each independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo, CN, OH, NR_(2a)R_(2b), SO₂R_(2c) and NHSO₂R_(2c); R_(2a) is selected from H and C₁₋₄ alkyl; R_(2b) is selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered heterocycloalkyl; R_(2c) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered heterocycloalkyl; each R₃ is independently halo, methyl, ethyl or n-propyl; m is 0, 1, 2, 3 or 4; wherein group (Ab) is:

wherein: R₄ is H, C₁₋₄ alkyl or C₁₋₄ alkylene(aryl); wherein said aryl is optionally substituted by 1, 2 or 3 substituents each independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo, CN, OH, NR_(4a)R_(4b), SO₂R_(4c) and NHSO₂R_(4c); R_(4a) is selected from H and C₁₋₄ alkyl; R_(4b) is selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered heterocycloalkyl; R_(4c) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered heterocycloalkyl; R₅ is H or C₁₋₄ alkyl; each R₆ is independently C₁₋₄ alkyl or halo; n is 0, 1, 2 or 3; wherein group (Ac) is:

wherein: R₇ is C₁₋₄ alkyl, C₁₋₄ alkylene(OH) or C₁₋₄ alkyleneOC₁₋₄ alkyl; o is 1 or 2; wherein group (Ad) is:

wherein: X is a bond, O or CH₂; each R₈ is independently halo, C₁₋₄ alkyl, C₁₋₄ alkoxy OC₁₋₄ haloalkyl, OC₁₋₄ alkylene(C₃₋₆ cycloalkyl), OC₁₋₄ alkylene(4-7 membered heterocycloalkyl) or OH; wherein said heterocycloalkyl and cycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo, CN, OH, NR_(8a)R_(8b), SO₂R_(8c) and NHSO₂R_(8c); R_(8a) is selected from H and C₁₋₄ alkyl; R_(8b) is selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered heterocycloalkyl; R_(8c) is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, aryl and 4-7 membered heterocycloalkyl; each R₉ is independently halo or C₁₋₄ alkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; wherein B is:

wherein: R₁₀ is H, halo or C₁₋₄ alkyl; D, E and F are each independently C(R₁₀); or one of D, E and F is N and the two remaining D, E and F groups are independently C(R₁₀); and provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and/or solvate thereof.
 58. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, which is a compound of formula (I):

wherein: R_(1a) is H or methyl; R_(1b) is H or fluoro; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is:

wherein: R₂ is H, C₁₋₄ alkyl, C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH), C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkylene(4-7 membered heterocycloalkyl), C₁₋₄ alkoxy, OC₁₋₄ alkylene(aryl), C₁₋₄ alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl), C₁₋₄ alkyleneO(aryl), C₃₋₆ alkynyl or C₁₋₄ alkyleneO(C₃₋₆ alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo and CN; each R₃ is independently halo, methyl, ethyl or n-propyl; m is 0, 1, 2, 3 or 4; wherein group (Ab) is:

wherein: R₄ is H, C₁₋₄ alkyl or C₁₋₄ alkylene(aryl); wherein said aryl may be optionally substituted by up to 3 substituents each independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo and CN; R₅ is H or C₁₋₄ alkyl; each R₆ is independently C₁₋₄ alkyl or halo; n is 0, 1, 2 or 3; wherein group (Ac) is:

wherein: R₇ is C₁₋₄ alkyl, C₁₋₄ alkylene(OH) or C₁₋₄ alkyleneOC₁₋₄ alkyl; o is 1 or 2; wherein group (Ad) is:

wherein: X is a bond, O or CH₂; each R₈ is independently halo, C₁₋₄ alkyl, C₁₋₄ alkoxy or OH; each R₉ is independently halo or C₁₋₄ alkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; wherein B is:

wherein: R₁₀ is H, halo or C₁₋₄ alkyl; and D, E and F are each independently C(R₁₀); or one of D, E and F is N and the two remaining D, E and F groups are independently C(R₁₀); provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and/or solvate thereof.
 59. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, wherein A is group (Aa):

wherein: R₂ is C₁₋₄ alkyl, C₁₋₄ alkylene(aryl), C₁₋₄ alkylene(OH), C₁₋₄ alkyleneOC₁₋₄ alkyl, C₁₋₄ alkyleneOC₃₋₆ cycloalkyl, C₁₋₄ alkyleneO(aryl), C₁₋₄ alkylene(4-7 membered heterocycloalkyl), C₁₋₄ alkyleneO (4-7 membered heterocycloalkyl) and C₁₋₄ alkyleneO(C₃₋₆ alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl; C₁₋₄ alkoxy, C₁₋₄ haloalkyl, halo and CN.
 60. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 59, wherein each R₃ is independently fluoro or methyl.
 61. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 59, wherein m is 1 or
 2. 62. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, wherein A is group (Ab):


63. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 62, wherein R₄ is H, methyl or benzyl, and R⁵ is H.
 64. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 62, wherein each R₆ is independently fluoro or methyl and n is
 0. 65. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, wherein A is group (Ac):


66. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 65, wherein R₇ is methyl, CH₂OH or CH₂OMe and o is
 2. 67. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, wherein A is group (Ad):


68. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 67, wherein X is a bond or O, p is 1 and R₈ is selected from methyl, OMe or fluoro.
 69. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 67, wherein each R₉ is independently fluoro and q is 1 or
 2. 70. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, wherein D, E and F are C(R₁₀).
 71. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, wherein each R₁₀ is independently H, fluoro, chloro or methyl.
 72. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, which is a compound of formula (Ia):

wherein A is group (Aa′), (AdI′) or (AdII′); R_(10a) is H, fluoro, chloro or methyl; wherein group (Aa′) is:

wherein: R_(2d) is methyl, CH₂OMe or CH₂OCH₂C≡CH; each R_(3a) is independently H, methyl or fluoro; and wherein group (AdI′) is:

wherein: R_(8d) is H, methyl or OMe; R_(9a) is H or F; wherein group (AdII′) is:

wherein: X is O; and R_(8a′) is methyl; provided that when A is group (AdI′) and one of R_(10a) is fluoro or chloro, the two remaining R_(10a) groups are independently H; or a pharmaceutically acceptable salt and/or solvate thereof.
 73. The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, which is selected from the group consisting of: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl) acrylamide (racemic mixture); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl) acrylamide (enantiomer 1); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl) acrylamide (enantiomer 2); (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide; (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 4); (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide; (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide; (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (mixture of stereoisomers); (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 1); (E)-N-((1R,3 S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 2); (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide; (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride; (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide; or a pharmaceutically acceptable salt and/or solvate of any one thereof.
 74. A method of preventing or treating a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt and/or solvate thereof according to claim
 57. 75. The method according to claim 74, wherein the disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia and re-perfusion injury, metabolic diseases, inflammatory or autoimmune diseases, diseases of aging and renal diseases, such as a degenerative or neurodegenerative disease selected from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontal temporal dementia, chemotherapy induced neuropathy, Huntington's disease, spinocerebellar ataxias, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury and Friedreich's ataxia.
 76. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 57, and a pharmaceutically acceptable carrier or excipient. 